2-thio-substituted imidazole derivatives and the use thereof in the pharmaceutical industry

ABSTRACT

The invention relates to 2-thio-substituted imidazole derivatives of the formula I 
                         
in which the radicals R 1 , R 2 , R 3  and R 4  are as defined in the description. The compounds according to the invention have immunomodulating and/or cytokine-release-inhibiting action and are therefore suitable for treating disorders associated with a disturbed immune system.

The present invention relates to 2-thio-substituted imidazole derivatives having immunomodulating and cytokine-release-inhibiting action, to pharmaceutical compositions comprising these compounds and to their use in pharmacy.

Pharmacologically active imidazole compounds with antiinflammatory activity are already known.

Thus, inter alia, compounds having 4,5-di(hetero)arylimidazole moieties have been examined more closely, and various pharmaceutical actions thereof have been described. Also known are compounds which are substituted in the 2-position.

U.S. Pat. No. 4,585,771 discloses 4,5-diphenylimidazole derivatives which are substituted in the 2-position by a pyrrolyl, indolyl, imidazolyl or thiazolyl radical and which have antiinflammatory and antiallergic activity.

U.S. Pat. Nos. 4,528,298 and 4,402,960 describe 4,5-di(hetero)arylimidazole derivatives which are substituted in the 2-position via a thio, sulfinyl or sulfonyl group by a phenyl, pyridyl, N-oxypyridyl, pyrimidyl, thiazolyl or thienyl radical and which have antiinflammatory and antiallergic activity.

U.S. Pat. Nos. 4,461,770 and 4,584,310 describe 4-(5-aryl)5-(4-heteroaryl)imidazole derivatives which are substituted in the 2-position via a thio, sulfinyl or sulfonyl group by a substituted or unsubstituted aliphatic hydrocarbon and which, inter alia, have antiinflammatory action.

DE 198 42 833 relates to 4-heteroaryl-5-phenylimidazole derivatives which are substituted in the 2-position by a phenylalkylthio group. These compounds act as antiinflammatories and inhibitors of cytokine release. WO 99/03837 and WO 93/14081 describe 2-substituted imidazoles which inhibit the synthesis of a number of inflammatory cytokines. The compounds described in WO 93/14081 have in the 2-position, attached via a sulfur atom, a phosphorus-containing substituent or an aryl or heteroaryl substituent. WO 91/10662 describes imidazole derivatives which inhibit the acyl-CoA: cholesterol 0-acyl transferase and binding of thromboxane TxA₂. WO 95/00501 describes imidazole derivatives which can be used as cyclooxygenase inhibitors. The imidazole derivatives described in DE 28 23 197 A have antiinflammatory, antiallergic and immunostimulating action.

J. Med. Chem. 1996, 39, 3927-37 describes compounds having 5-lipoxygenase- and cyclooxygenase-inhibiting action, 2-(4-methylsulfinylphenyl)-4-(4-fluorophenyl-5-(pyrid-4-yl)imidazole also having cytokine-inhibiting action.

It has been found that the known compounds are unstable and difficult to process, or that their efficacy is low.

In spite of the fact that numerous compounds are known, there is therefore still a need for compounds having antiinflammatory action which inhibit cytokine release.

It is an object of the invention to provide such compounds.

Surprisingly, it has now been found that certain 2-substituted imidazole derivatives provide stable compounds which are readily processible and which have high immunomodulating and/or cytokine-release-inhibiting activity.

Accordingly, the present invention provides 2-thio-substituted imidazole derivatives of the formula I

where

-   -   R¹ is selected from the group consisting of:     -   C₁-C₆-alkyl which is unsubstituted or substituted by one or two         hydroxyl or C₁-C₄-alkoxy groups or by a nonaromatic heterocyclic         radical having 5 or 6 ring atoms and 1 or 2 heteroatoms         independently of one another selected from the group consisting         of N, O and S,     -   C₂-C₆-alkenyl,     -   C₃-C₆-cycloalkyl,     -   aryl which is unsubstituted or substituted by one or more         halogen atoms or by a C₁-C₄-alkylsulfanyl group,     -   amino-C₁-C₄-alkyl, where the amino group is unsubstituted or         substituted by one or two C₁-C₄-alkyl groups,     -   aminoaryl, where the amino group is unsubstituted or substituted         by one or two C₁-C₄-alkyl groups,     -   aryl-C₁-C₄-alkyl or     -   an aromatic or nonaromatic heterocyclic radical having 5 or 6         ring atoms and 1 or 2 heteroatoms independently of one another         selected from the group consisting of N, O and S, which         heterocyclic radical is unsubstituted or substituted by 1, 2, 3         or 4 C₁-C₄-alkyl groups, an aryl or aryl-C₁-C₄-alkyl group,     -   R² is selected from the group consisting of:     -   H;     -   C₁-C₆-alkyl,     -   phenyl-C₁-C₄-alkyl, where the phenyl group may have one or two         substituents independently of one another selected from the         group consisting of C₁-C₄-alkyl, halogen, C₁-C₄-alkylsulfanyl,         C₁-C₄-alkylsulfinyl and C₁-C₄-alkylsulfonyl,     -   C₂-C₆-alkenyl,     -   C₂-C₆-alkenyl which is substituted by one or two halogen atoms         and/or phenyl groups, where the phenyl group may independently         be substituted by one or two C₁-C₄-alkyl or halogen atoms,     -   C₂-C₆-alkynyl,     -   C₂-C₆-alkynyl which is substituted by a phenyl group which may         be unsubstituted or substituted by one or two C₁-C₄-alkyl or         halogen atoms,     -   C₁-C₆-alkyl which is substituted by a nonaromatic heterocyclic         radical having 5 or 6 ring atoms and 1 or 2 heteroatoms         independently of one another selected from the group consisting         of N, O and S, C₁-C₄-alkylsulfanyl, C₁-C₄-alkylsulfinyl or         C₁-C₄-alkylsulfonyl,     -   phenyl or     -   phenyl which has one or two substituents independently of one         another selected from the group consisting of C₁-C₄-alkyl,         halogen, C₁-C₄-alkylsulfanyl, C₁-C₄-alkylsulfinyl and         C₁-C₄-alkylsulfonyl, or     -   R¹ and R² together are —CH₂CH₂— or —CH₂CH₂CH₂—,     -   one of the radicals R³ and R⁴ is C₁-C₆-alkyl or an aromatic         heterocyclic radical having 5 or 6 ring atoms and 1 or 2         heteroatoms independently of one another selected from the group         consisting of N, O and S, where the aromatic heterocyclic         radical may have 1 or 2 substituents independently of one         another selected from the group consisting of C₁-C₆-alkyl,         amino, C₁-C₄-alkylamino, di-C₁-C₄-alkylamino,         phenyl-C₁-C₄-alkylamino and R⁵CONR⁶—, where R⁵ is C₁-C₄-alkyl,         phenyl, which may have one or two substituents independently of         one another selected from the group consisting of C₁-C₄-alkyl,         C₁-C₄-alkoxy and halogen, or C₃-C₆-cycloalkyl and R⁶ is H,         C₁-C₄-alkyl or benzyl, and     -   the second of the radicals R³ and R⁴ is C₁-C₆-alkyl or aryl         which is unsubstituted or substituted by a halogen atom, where         only one of the radicals R³ and R⁴ may be C₁-C₆-alkyl,     -   with the proviso that, if R¹ represents aryl-C₁-C₅-alkyl or         amino-C₁-C₆-alkyl, R² represents alkylsulfonyl- or         alkylsulfinylaryl-C₁-C₅-alkyl, their optical isomers and         physiologically acceptable salts.

Preference is given to compounds of the formula I in which R¹ is C₁-C₆-alkyl which is unsubstituted or substituted by one or two hydroxyl groups or a nonaromatic heterocyclic radical, C₂-C₆-alkenyl, C₃-C₆-cycloalkyl, aryl which is unsubstituted or substituted by one or more halogen atoms or a C₁-C₄-alkylsulfanyl group, amino-C₁-C₄-alkyl, where the amino group is unsubstituted or substituted by one or two C₁-C₄-alkyl groups, aminoaryl, where the amino group is unsubstituted or substituted by one or two C₁-C₄-alkyl groups, aryl-C₁-C₄-alkyl or an aromatic or nonaromatic heterocyclic radical having 5 or 6 ring atoms and 1 or 2 heteroatoms independently of one another selected from the group consisting of N, O and S, which heterocyclic radical is unsubstituted or substituted by 1, 2, 3 or 4 C₁-C₄-alkyl groups, an aryl or aryl-C₁-C₄-alkyl group,

-   -   R² is H, C₁-C₆-alkyl, phenyl-C₁-C₄-alkyl, where the phenyl group         may have one or two substituents independently of one another         selected from the group consisting of C₁-C₄-alkyl, halogen,         C₁-C₄-alkylsulfanyl, C₁-C₄-alkylsulfinyl and         C₁-C₄-alkylsulfonyl, C₂-C₆-alkenyl, C₂-C₆-alkenyl which is         substituted by one or two halogen atoms and/or phenyl groups,         where the phenyl group may independently be substituted by one         or two C₁-C₄-alkyl or halogen atoms, C₂-C₆-alkynyl,         C₂-C₆-alkynyl which is substituted by a phenyl group which may         be unsubstituted or substituted by one or two C₁-C₄-alkyl or         halogen atoms, C₁-C₆-alkyl which is substituted by a nonaromatic         heterocyclic radical having 5 or 6 ring atoms and 1 or 2         heteroatoms independently of one another selected from the group         consisting of N, O and S,     -   one of the radicals R³ and R⁴ is C₁-C₆-alkyl or an aromatic         heterocyclic radical having 5 or 6 ring atoms and 1 or 2         heteroatoms independently of one another selected from the group         consisting of N, O and S, where the aromatic heterocyclic         radical may have 1 or 2 substituents independently of one         another selected from the group consisting of C₁-C₆-alkyl,         amino, C₁-C₄-alkylamino, di-C₁-C₄-alkylamino,         phenyl-C₁-C₄-alkylamino, R⁵CONR⁶—, where R⁵ is C₁-C₄-alkyl,         phenyl which may have one or two substituents independently of         one another selected from the group consisting of C₁-C₄-alkyl,         C₁-C₄-alkoxy and halogen, or C₃-C₆-cycloalkyl, and R⁶ is H,         C₁-C₄-alkyl or benzyl, and the second of the radicals R³ and R⁴         is C₁-C₆-alkyl or aryl which is unsubstituted or substituted by         a halogen atom, where only one of the radicals R³ and R⁴ may be         C₁-C₆-alkyl.

If the compounds according to the invention have centers of asymmetry, the scope of the invention includes both racemates and optical isomers (enantiomers, diastereomers).

The term “alkyl” (also in combination with other groups, such as phenylalkyl, alkylsulfonyl, etc.) embraces straight-chain and branched alkyl groups having preferably 1 to 6 or 1 to 4 carbon atoms, such as methyl, ethyl, n- and i-propyl, n-, i- and t-butyl, sec-butyl, n-pentyl and n-hexyl.

The term “aryl” embraces aromatic ring systems, such as phenyl or naphthyl.

The term “halogen” represents a fluorine, chlorine, bromine or iodine atom, in particular a fluorine or chlorine atom.

C₃-C₆-Cycloalkyl groups are cyclopropyl, cyclobutyl and, in particular, cyclopentyl and cyclohexyl.

Nonaromatic heterocyclic radicals can be saturated or unsaturated. Preference is given to piperidinyl, piperazinyl, pyranyl, morpholinyl or pyrrolidinyl, where the piperidinyl radical may be substituted by 1, 2, 3 or 4 C₁-C₄-alkyl groups, in particular methyl groups.

Preferred aromatic heterocyclic radicals are pyridyl, in particular 3- or 4-pyridyl, pyrimidinyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, furyl, thienyl or thiazolyl. The heterocyclic radical, in particular the pyridyl radical, may be substituted as mentioned above. The pyridyl radical is substituted in particular in the 2-position.

Phenyl-C₁-C₄-alkyl is in particular benzyl or phenylethyl.

Preference is given to compounds of the formula I in which one of the radicals R³ and R⁴ is C₁-C₄-alkyl or a halogen-substituted phenyl and the second of the radicals R³ and R⁴ is C₁-C₄-alkyl or pyridyl or substituted pyridyl, with the proviso, that the two radicals are not both C₁-C₄-alkyl.

Preference is furthermore given to compounds of the formula I where R³ is halogen-substituted, in particular 4-substituted, phenyl and R⁴ is unsubstituted or substituted pyridyl, in particular 4-pyridyl or substituted 4-pyridyl.

According to a particularly preferred embodiment, the radical R³ in the formula I is 4-fluorophenyl and R⁴ is 4-pyridyl or substituted pyridyl.

If R¹ is C₁-C₆-alkyl which is substituted by a nonaromatic heterocyclic radical, this radical preferably contains at least one nitrogen atom, and the attachment to the alkyl group is preferably via the nitrogen atom.

If R¹ is an aromatic or nonaromatic heterocyclic radical, this is preferably attached to the imidazole group via a carbon atom.

R¹ is preferably C₁-C₃-alkyl, C₃-C₆-cycloalkyl, in particular cyclopropyl, or a saturated heterocyclic radical having one or two nitrogen atoms, in particular piperidinyl or 2,2,6,6-tetramethylpiperidinyl. With particular preference, the piperidinyl or 2,2,6,6-tetramethylpiperidinyl radical is attached in the 4-position to the nitrogen atom of the imidazole.

R² is preferably C₁-C₃-alkyl (methyl, ethyl, n-propyl or i-propyl) or phenyl-C₁-C₄-alkyl, in particular benzyl, which may be substituted as stated above. With particular preference, R² is C₁-C₃-alkyl or benzyl which is substituted by C₁-C₄-alkylsulfanyl, C₁-C₄-alkylsulfinyl or C₁-C₄-alkylsulfonyl, in particular in the 4-position.

Particular preference is given to compounds of the formula in which R⁴ is pyridyl, in particular 4-pyridyl, which is substituted by amino, C₁-C₄-alkylamino or R⁵COR⁶-, where R⁵ and R⁶ are as defined above, R¹ is C₁-C₃-alkyl and R² is C₁-C₃-alkyl.

In the present case, the physiologically acceptable salts can be acid addition salts or base addition salts. For acid addition salts, inorganic acids, such as hydrochloric acid, sulfuric acid or phosphoric acid, or organic acids, such as tartaric acid, citric acid, maleic acid, fumaric acid, malic acid, mandelic acid, ascorbic acid, gluconic acid and the like, are used.

The compounds according to the invention where R²≠H are prepared in a two-step process. In the first step, initially a substituted imidazole-2-thione (R²=H) is prepared. This is then reacted in the second step such that the desired substituent is introduced.

1) Preparation of the imidazole-2-thione

Two process variants are available for preparing the imidazole-2-thione. The two variants are illustrated in an exemplary manner using compounds in which R³ is 4-fluorophenyl and R⁴ is 4-pyridyl. Compounds having other radicals R³ and R⁴ can be prepared in an analogous manner.

Variant 1

The synthesis of the substituted imidazole-2-thiones is carried out according to the course of the reaction of scheme 1, using ethyl isonicotinate and 4-fluorophenyl-acetonitrile as starting materials.

The starting materials are converted in a condensation reaction with the aid of metallic sodium in an alcohol, for example ethanol, into 2-cyano-2-(4-fluorophenyl)-1-(4-pyridyl)ethanone (compound 1). The cyano group is then removed by hydrolysis, for example with hydrobromic acid, and decarboxylation, giving 2-(4-fluorophenyl)-1-(4-pyridyl)ethanone (compound 2). In the next step, compound 2 is nitrosated in the 2-position using, for example, nitrites, such as sodium nitrite or isoamyl nitrite.

This gives the compound of the formula (3), the oxime 2-(4-fluorophenyl)-1-(4-pyridyl)-α-hydroxyiminoethane.

Using this intermediate, cyclization giving an imidazole derivative of the formula (4), a substituted 5-(4-fluorophenyl)-4-(4-pyridyl)imidazole N-oxide which carries the substituent R¹ at the nitrogen atom in 3-position, is carried out by reaction with an imine of the general formula H₂C═NR₁, which is present as a 1,3,5-trisubstituted hexahydro-1,3,5-triazine, in an alcoholic solvent, such as ethanol, and at elevated temperature (50-90° C.). The imidazole N-oxide of the formula (4) is then reacted with 2,2,4,4-tetramethyl-3-thiocyclobutanone in a chlorinated solvent to give the corresponding 3-substituted 5-(4-fluorophenyl)-4-(4-pyridyl)imidazole-2-thione (compound 5; compound of the formula I where R²═H).

Variant 2

Initially, the oxime compound of the formula (3), 2-(4-fluorophenyl)-1-(4-pyridyl)-α-hydroxyiminoethane, is prepared as described in variant 1 (scheme 1, steps 1 to 3). Using this starting material, the synthesis of the substituted imidazole-2-thiones is carried out according to scheme 2.

2-(4-Fluorophenyl)-1-(4-pyridyl)-α-hydroxyiminoethane is, according to scheme 2, reacted with the selected amine of the general formula NH₂—R₁ and formaldehyde, giving, with ring closure, a compound of the formula (6), i.e. a 1-substituted 4-(4-fluorophenyl)-5-(4-pyridyl)imidazol-2-one. This is reacted with an excess of phosphorus oxychloride, resulting in a compound of the formula (7), i.e. a 1-substituted 4-(4-fluorophenyl)-5-(4-pyridyl)imidazole 2-chloride being formed. From this compound, the corresponding 1-substituted 4-(4-fluorophenyl)-5-(4-pyridyl)-imidazole-2-thione (compound 5) is obtained by reaction with 4-chlorobenzylthiol in a polar aprotic solvent and at elevated temperature (100-150° C.).

2) Preparation of the 2-thioimidazole compound

The thione compounds (5) obtained according to variant 1 or 2 are converted by substitution of the sulfur atom in the 2-position into the compounds of the formula I according to the invention where R²≠H. The substitutions can be carried out in a known manner by a nucleophilic substitution reaction, as shown in an exemplary manner for some compounds in scheme 3. Here, compound 5 is reacted with R²—X in an inert polar solvent, such as an alcohol. X is a readily exchangeable group, such as Hal, in particular Cl, Br, I, methylsulfonyl, tosyl etc.

2-Thioimidazole compounds in which the sulfur atom [lacuna] 2-position is substituted by a vinyl radical can be obtained by nucleophilic addition of compound 5 to a triple bond. To this end, 5 is reacted with a base, for example an alkali metal alkoxide in the corresponding alcohol, and then with an excess of the compound with the triple bond.

The corresponding bisaryl thioethers are prepared from the 3-substituted 2-chloro-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole (compound 7 from scheme 2). The compounds (7) are reacted with two equivalents of the appropriate thiophenol in an aprotic solvent, such as dimethylformamide, giving compounds of the formula (12).

The corresponding regioisomeric compounds can be prepared in accordance with scheme (5). Starting with 1-(4-fluorophenyl)-2-(4-pyridyl)-α-hydroxyiminoethanone (obtained analogously to scheme 1), compounds of the formula 15 are obtained analogously to the process of scheme 1 by reaction with the appropriate imines. Compound (13) can be prepared by the process described in WO 93/14081.

These compounds can be reacted further as described in scheme 3.

The imidazolethiols which carry a C₁-C₄-alkyl group in the 4-position are obtained from the corresponding α-hydroxyiminoethanones (compound 17/19 in scheme 6 below), analogously to schemes 1 and 2.

These compounds can be reacted further according to schemes 3 and 4. The corresponding regioisomeric compounds can be prepared analogously to scheme 5.

Compounds of the formula I which carry a C₁-C₄-alkylsulfanyl radical can be oxidized by known processes, using a suitable oxidizing agent, such as m-chloroperbenzoic acid, hydrogen peroxide, benzoyl peroxide, etc., to give the corresponding C₁-C₄-alkylsulfinyl or C₁-C₄-alkylsulfonyl compound, see scheme 7.

The preparation of the compounds in which R⁴ is an amino- or amido-substituted heterocyclic radical, in particular a pyridyl radical, is carried out according to scheme 8, where the preparation is illustrated using 2-substituted 4-pyridine compounds as examples (compounds in which R⁴ is an alkyl-substituted heterocyclic radical are prepared by the processes mentioned above using appropriately substituted starting materials):

The amino group of the starting material 2-amino-γ-picolin (24) is protected, for example by introduction of an acetyl group using acetic anhydride. The methyl group of the compound (25) is then oxidized to the carboxyl group using, for example, potassium permanganate in an aqueous medium at from 20 to 90° C.

The reaction of the resulting pyridinecarboxylic acid (26) with 4-fluorophenyl-acetonitrile to give compound (27) and the subsequent removal of the nitrile group are carried out in accordance with variant 1. This also results in the removal of the acetyl group on the amino group of the pyridine compound, with the compound (28) being formed.

In the next step, the amino group is again protected, for example by introducing an acetyl group using acetic anhydride. The resulting compound (29) is, in accordance with variant 1 or 2 (shown in scheme 8 using variant 1), converted into the thiono compound (32). Into this compound, the desired radical R² is introduced as described in schemes 3, 4 and 7.

To introduce the desired substituent into the pyridyl group, the acetyl group is initially removed hydrolytically, for example using aqueous acid, giving the amino compound (35). An acyl radical is introduced by acylation, in particular with the corresponding acid chloride R⁵COCl in an inert solvent, such as an ether, for example tetrahydrofuran or dioxane, or in a chlorinated hydrocarbon, for example methylene chloride or 1,2-dichloroethan, etc. The acylation is generally carried out in the presence of a base, for example triethylamine, in an at least equimolar amount.

To prepare the substituted amine compounds, compound (35) is reacted with one or two molar equivalents of an alkyl bromide or phenylalkyl bromide in an inert solvent, such as dimethylformamide, in the presence of a base, such as sodium hydride, to give the compounds (37) or (38). Alternatively, the amide compounds (34) or (36) can be reduced with lithium aluminum hydride, for example in tetrahydrofuran, to give compound 39.

In vitro and in vivo, the compounds according to the invention show immunomodulating and cytokine-release inhibiting action. Cytokines are proteins such as TNF-α and IL-β which play an important role in numerous inflammatory disorders. The compounds according to the invention are, owing to their cytokine-release-inhibiting action, suitable for treating disorders which are associated with a disturbance of the immune system. They are suitable, for example, for treating autoimmune disorders, cancer, rheumatoid arthritis, gout, septic shock, osteoporosis, neuropathic pain, the spread of HIV, HIV dementia, viral myocarditis, insulin-dependent diabetes, periodontal disorders, restenosis, alopecia, T-cell depletion associated with HIV infections or AIDS, psoriasis, acute pancreatitis, rejection reactions of allogenic transplants, allergic pneumonia, arteriosclerosis, multiple sclerosis, cachexia, Alzheimer's disease, stroke, ictus, colitis ulcerosa, morbus Crohn, inflammatory bowel disease (IBD), ischemia, congestive heart failure, pulmonary fibrosis, hepatitis, glioblastoma, Guillain-Barre syndrome, systemic lupus erythematodes, adult respiratory distress syndrome (ARDS) and respiratory distress syndrome.

The compounds according to the invention can be administered either as individual therapeutically active compounds or as mixtures with other therapeutically active compounds. The compounds can be administered on their own; in general, however, they are formulated and administered in the form of pharmaceutical compositions, i.e. as mixtures of the active compounds with suitable pharmaceutical carriers or diluents. The compounds or compositions can be administered orally or parenterally; preferably, they are administered in oral dosage forms.

The type of pharmaceutical composition or carrier or diluent depends on the desired administration form. Oral compositions, for example, can be present as tablets or capsules and may comprise customary excipients, such as binders (for example syrup, gum arabic, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone), fillers (for example lactose, sugar, cornstarch, calcium phosphate, sorbitol or glycerol), glidants (for example magnesium stearate, talc, polyethylene glycol or silica), disintegrants (for example starch) or wetting agents (for example sodium lauryl sulfate). Liquid oral preparations can assume the form of aqueous or oily suspensions, solutions, emulsions, syrups, elixirs or sprays and the like. They can also be present as a dry powder which is reconstituted using water or another suitable carrier. Such liquid preparations may comprise customary additives, for example suspending agents, flavors, diluents or emulsifiers. For parenteral administration, it is possible to use solutions or suspensions with customary pharmaceutical carriers.

The compounds or compositions according to the invention can be administered to mammals (man or animal) in a dose of from about 0.5 mg to 100 mg per kg of body weight per day. They may be administered in one individual dose or in a plurality of doses. The activity spectrum of the compounds as inhibitors of cytokine release was examined using the test systems below, as described by C. Donat and S. Laufer in Arch. Pharm. Pharm. Med. Chem. 333, Suppl. 1, 1-40, 2000.

In vitro Test with Human Whole Blood

The test substance is added to samples of human potassium-EDTA whole blood (of 400 μl each) and the samples are preincubated in a CO₂ incubator (5% CO₂; 95% moisture-saturated air) at 37° C. for 15 min. The samples are then stimulated with 1 μg/ml of LPS (E.coli 026:B6) at 37° C. in a CO₂ incubator (5% CO₂; 95% moisture-saturated air) for 4 hours. The reaction is stopped by placing the samples on ice, adding DPBS buffer and then centrifuging at 1000*g for 15 min. The amount of IL-1β and TNFα in the plasma supernatant is then determined by ELISA.

In vitro Test with PBMCs

The mononuclear cells (PBMCs) from human potassium-EDTA whole blood, diluted 1:3, are isolated by density gradient centrifugation (Histopaque®-1.077). The cells are washed twice with DPBS buffer, resuspended in macrophage SFM medium and adjusted to a cell count of 1*10⁶ cells/ml.

The resulting PBMCs suspension (samples of in each case 390 μl) and the test substance are preincubated at 37° C. in a CO₂ incubator (5% CO₂; 95% moisture-saturated air) for 15 min. The samples are then stimulated with in each case 1 μl/ml of LPS (E.coli 026:B6) at 37° C. in a CO₂ incubator (5% CO₂; 95% moisture-saturated air) for 4 hours. The reaction is stopped by placing the samples on ice, adding DPBS buffer and then centrifuging at 15 880*g for 12 min. The amount of IL-1β and TNFα in the plasma supernatant is then determined by ELISA.

The results of the in vitro tests are shown in tables 1 and 2 below.

TABLE 1

Ex- ample R1 R2 R3 R4 Yield^(b)) TNF-α^(a)) IL-1β^(a)) 1 CH₃ H 4-F-phenyl 4-pyridyl 36 19 3.6 2 C₂H₅ H 4-F-phenyl 4-pyridyl 11 41 1.3 3 n-C₃H₇ H 4-F-phenyl 4-pyridyl 31/22 32 2.4 4 i-C₃H₇ H 4-F-phenyl 4-pyridyl 15 46% 2.2 5 cyclohexyl H 4-F-phenyl 4-pyridyl 9 33 5.4 6 cyclopropyl H 4-F-phenyl 4-pyridyl 33 —^(b)) — 7 phenyl H 4-F-phenyl 4-pyridyl 7 37 2.3 8 benzyl H 4-F-phenyl 4-pyridyl 8 20 1.0 9 4-dimethylaminophenyl H 4-F-phenyl 4-pyridyl 8 15 1.8 10 3-pyridyl H 4-F-phenyl 4-pyridyl 16 42% 8.0 11 dimethylaminoethyl H 4-F-phenyl 4-pyridyl 15 19% 12 12 2,2,6,6-tetramethylpiperidin- H 4-F-phenyl 4-pyridyl 13 45 1.6 4-yl 13 dimethylaminopropyl H 4-F-phenyl 4-pyridyl 22 — — 14 N-morpholinopropyl H 4-F-phenyl 4-pyridyl 38 100 18 15 4-methylsulfanylphenyl H 4-F-phenyl 4-pyridyl 13 — — 16 N-morpholinoethyl H 4-F-phenyl 4-pyridyl 16 34% 44% 17 3-hydroxypropyl H 4-F-phenyl 4-pyridyl 13 49% 7.3 18 1-benzylpiperidin-4-yl H 4-F-phenyl 4-pyridyl 18 38 5.8 19 allyl H 4-F-phenyl 4-pyridyl 28 — — 20 CH₃ CH₃ 4-F-phenyl 4-pyridyl 15 2.5 0.45 21 n-C₃H₇ CH₃ 4-F-phenyl 4-pyridyl 6 1.3 0.36 22 cyclopropyl CH₃ 4-F-phenyl 4-pyridyl 12 1.1 0.34 23 N-morpholinoethyl CH₃ 4-F-phenyl 4-pyridyl 3 24 N-morpholinopropyl CH₃ 4-F-phenyl 4-pyridyl 4 2.7 1.0 25 2,2,6,6-tetramethylpiperidin- CH₃ 4-F-phenyl 4-pyridyl 11 16 0.85 4-yl 26 1-benzylpiperidin-4-yl CH₃ 4-F-phenyl 4-pyridyl 3 — — 27 C₂H₅ 4-CH₃—SO₂-benzyl 4-F-phenyl 4-pyridyl 6 4.1 0.95 28 n-C₃H₇ benzyl 4-F-phenyl 4-pyridyl 24 29 0.65 29 n-C₃H₇ 4-Cl-benzyl 4-F-phenyl 4-pyridyl 20 62 1.3 30 n-C₃H₇ 4-CH₃-benzyl 4-F-phenyl 4-pyridyl 20 22 1.3 31 n-C₃H₇ 4-CH₃—S-benzyl 4-F-phenyl 4-pyridyl 12 35% 4.7 32 n-C₃H₇ 4-CH₃—SO-benzyl 4-F-phenyl 4-pyridyl 3 24 1.6 33 n-C₃H₇ 4-CH₃—SO₂-benzyl 4-F-phenyl 4-pyridyl 9 6.8 0.72 34 i-C₃H₇ 4-Cl-benzyl 4-F-phenyl 4-pyridyl 6 53 5.3 35 i-C₃H₇ 4-CH₃—SO₂-benzyl 4-F-phenyl 4-pyridyl 7 2.7 1.5 36 cyclopropyl —CH₂—CH═CH-phenyl 4-F-phenyl 4-pyridyl 27 — — 37 cyclopropyl —CH₂—CH═CH-4-Cl- 4-F-phenyl 4-pyridyl 11 — — phenyl (trans) 38 cyclopropyl —CH₂—CH═CH-phenyl 4-F-phenyl 4-pyridyl 12 — — 39 cyclohexyl 4-CH₃—SO₂-benzyl 4-F-phenyl 4-pyridyl 5 13 1.8 40 phenyl 4-CH₃—SO₂-benzyl 4-F-phenyl 4-pyridyl 2 3.4 1.3 41 benzyl 4-CH₃—SO₂-benzyl 4-F-phenyl 4-pyridyl 3 1.0 0.36 42 N-morpholinoethyl benzyl 4-F-phenyl 4-pyridyl 5 11 1.3 43 N-morpholinopropyl benzyl 4-F-phenyl 4-pyridyl 25 5.4 0.89 44 N-morpholinopropyl 4-CH₃—SO₂-benzyl 4-F-phenyl 4-pyridyl 31 12 1.4 45 N-morpholinopropyl 4-CH₃—SO-benzyl 4-F-phenyl 4-pyridyl 4 12 2.4 46 2,2,6,6-tetramethylpiperidin- benzyl 4-F-phenyl 4-pyridyl 9 12 0.87 4-yl 47 CH₃ N-morpholinoethyl 4-F-phenyl 4-pyridyl 26 28 1.7 48 CH₃ cis-phenylethenyl 4-F-phenyl 4-pyridyl 10 22 1.7 49 n-C₃H₇ cis-phenylethenyl 4-F-phenyl 4-pyridyl 20 — — 50 cyclopropyl cis-phenylethenyl 4-F-phenyl 4-pyridyl 3 — — 51 n-C₃H₇ —CHBr—CHBr-phenyl 4-F-phenyl 4-pyridyl 20 — — 52 n-C₃H₇ phenyl 4-F-phenyl 4-pyridyl 26 14 1.0 53 n-C₃H₇ 4-Cl-phenyl 4-F-phenyl 4-pyridyl 25 29 3.3 54 n-C₃H₇ 4-CH₃—S-phenyl 4-F-phenyl 4-pyridyl 22 68 2.5 55 n-C₃H₇ 4-CH₃—SO-phenyl 4-F-phenyl 4-pyridyl 16 6.2 0.72 56 n-C₃H₇ 4-CH₃—SO₂-phenyl 4-F-phenyl 4-pyridyl 15 19 1.5 57 4-F-phenyl H CH₃ 4-pyridyl 7 34% 19 58 3-pyridyl H 4-F-phenyl CH₃ 15 32% 28 59 n-C₃H₇ H 4-pyridyl 4-F-phenyl 5 83 16% 60 N-morpholinoethyl H 4-pyridyl 4-F-phenyl 5 — — ^(a))IC₅₀[μmol x l⁻¹] ^(b))Total yield [%] for all steps

TABLE 2

Ex. R1 R7 R2 TNF-α^(a)) IL-1β^(a)) 61 CH₃ —COCH₃ CH₃ 0.87 0.07 62 C₃H₇ —COCH₃ CH₃ 0.49 0.12 63 2,2,6,6-tetramethylpiperidin-4-yl —COCH₃ CH₃ 4.5 0.46 64 N-morpholinopropyl —COCH₃ CH₃ — — 65 3-hydroxypropyl —COCH₃ CH₃ — — 66 CH₃ —H CH₃ 2.3 0.27 67 CH₃ -p-methoxybenzoyl CH₃ 0.64 0.44 68 CH₃ —CO-cyclopropyl CH₃ — — 69 CH₃ —CO-cyclopentyI CH₃ — — 70 CH₃ —Bz CH₃ 0.39 0.08 71 CH₃ -1-phenylethyl CH₃ 0.13 0.01 73 CH₃ —C₂H₅ CH₃ 0.35 0.05 74 C₃H₇ —C₂H₅ CH₃ 0.41 0.15 75 2,2,6,6-tetramethylpiperidin-4-yl —C₂H₅ CH₃ 2.9 0.62 76 N-morpholinopropyl —COCH₃ 4-methylsulfinylbenzyl — — ^(c))IC₅₀[μmol × l⁻¹] Bz = benzyl

The compounds according to the invention and the processes for their preparation are now described in more detail using the examples below, without limiting the invention.

EXAMPLES Example 1 4-(4-fluorophenyl)-1-methyl-5-(4-pyridyl)-2-thioimidazole

a) 2-Cyano-2-(4-fluorophenyl)-1-(4-pyridyl)ethane

250 ml of dry ethanol were added dropwise to metallic sodium (17.3 g/0.7 mol). Ethyl isonicotinate (75.8 g/0.5 mol) and 4-fluorophenylacetonitrile (67.6 g/0.5 mol) were then added dropwise, and the mixture was subsequently heated under reflux for 15 min. After cooling, 600 ml of distilled water were added to the mixture. When the mixture was acidified to pH 1 using concentrated hydrochloric acid (HCl), the desired compound 2-cyano-2-(4-fluorophenyl)-1-(4-pyridyl)ethane precipitated as a yellow precipitate. The precipitate was filtered off, washed with distilled water and dried under reduced pressure over phosphorus pentoxide (P₂O₅). The yield was 85.0 g (62%).

b) 2-(4-Fluorophenyl)-1-(4-pyridyl)ethanone

2-Cyano-2-(4-fluorophenyl)-1-(4-pyridyl)ethane (40.6 g/0.15 mol) from example 1a was suspended in 300 ml of 48% strength hydrobromic acid (HBr), and the reaction mixture was heated under reflux for 18 h. After cooling, the mixture was adjusted to pH 9 using aqueous ammonia. The compound mentioned in the title, which precipitated during this operation, was filtered off, washed with distilled water and dried under reduced pressure over P₂O₅. The yield was 25.6 g (80%).

c) 2-(4-Fluorophenyl)-1-(4-pyridyl)-α-hydroxyiminoethanone

15.0 g (0.07 mol) of 2-(4-fluorophenyl)-1-(4-pyridyl)ethanone from example 1b were dissolved in 70 ml of glacial acetic acid. A solution of 4.8 g (0.07 mol) of NaNO₂ in 11 ml of water was slowly added dropwise to the initial charge, and the reaction mixture was stirred at room temperature. After 3 h, 400 ml of distilled water were added, and the mixture was stirred at room temperature for another 3 h. The compound (3) mentioned in the title precipitated out. The compound was filtered off, washed with distilled water and dried under reduced pressure over P₂O₅. The yield was 15.2 g (90%).

d) 4-(4-Fluorophenyl)-1-methyl-5-(4-pyridyl)imidazole N-oxide

2.0 g of 2-(4-fluorophenyl)-1-(4-pyridyl)-α-hydroxyiminoethanone from example 1c above and twice the equivalent amount of 1,3,5-trimethylhexahydro-1,3,5-triazine were dissolved in 20 ml of dry ethanol and heated under reflux for 10 h. After cooling, the ethanol was removed using a rotary evaporator. The slightly oily residue solidified on addition of diethyl ether. The precipitate was filtered off and dried under reduced pressure. The yield was 82%.

e) 4-(4-Fluorophenyl)-1-methyl-5-(4-pyridyl)imidazole-2-thione

0.5 g of 5-(4-fluorophenyl)-4-(4-pyridyl)-3-methylimidazole N-oxide from example 1d were dissolved in 20 ml of CHCl₃, and the reaction mixture was cooled in an ice-bath. An equimolar solution of 2,2,4,4-tetramethyl-3-thionocyclobutanone in CHCl₃ was slowly added dropwise to the initial charge, and the mixture was then stirred in the ice-bath for 30 min. The ice-bath was removed, and stirring was continued at room temperature for 1 h. The solvent was then removed using a rotary evaporator, and the solid residue was triturated in diethyl ether. The precipitate was filtered off and dried under reduced pressure. The yield was 98%.

IR: 1/λ (cm⁻¹)=1601, 1506, 1229, 1004, 843, 832

¹H NMR (d₆-DMSO, ppm): 12.95 (bs, 1H), 8.69-8.66 (m, 2H), 7.45-7.42 (m, 2H), 7.27-7.12 (m, 4H), 3.39 (s, 3H)

Example 2 1-Ethyl-4-(4-fluorophenyl)-5-(4-pyridyl)-2-thioimidazole

a) 1-Ethyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazol-2-one

Initially, 2-(4-fluorophenyl)-1-(4-pyridyl)-α-hydroxyiminoethanone was prepared as described in example 1, steps (a) to (c). 4.0 g of the iminoethanone were then, together with the equimolar amount of ethylamine and the equimolar amount of formaldehyde (36% strength aqueous solution), heated under reflux for 4 h. After cooling, the reaction mixture was neutralized using aqueous ammonia and extracted three times with CH₂Cl₂. The organic phases were combined and dried over Na₂SO₄. The drying agent was filtered off and the solvent was removed using a rotary evaporator. The slightly oily residue was solidified by addition of diethyl ether. The precipitate was filtered off and dried under reduced pressure. The yield was 63%.

b) 2-Chloro-1-ethyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole

35 ml of POCl₃ and a small amount of NH₄Cl were added to 2.0 g of 1-ethyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazol-2-one, and the reaction mixture was heated under reflux for 9 h. After cooling, most of the excess POCl₃ was distilled off, and distilled water was carefully added to the residue. The mixture was neutralized using 20% strength NaOH, resulting in the precipitation of the title compound. The precipitate was filtered off and dried over P₂O₅ under reduced pressure. Yield: 81%.

c) 1-Ethyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole-2-thione

NaH (4.5 eq.) was suspended in 10 ml of DMF, and 4-chlorobenzylthiol (4.5 eq.) was slowly added dropwise. The reaction mixture was stirred at room temperature for 45 min. 2.0 g of the 2-chloro-1-ethyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole obtained in the step above were then added. The mixture was heated under reflux for 10 h. After cooling, distilled water was added to the mixture, the pH was adjusted to 1 using concentrated HCl and the mixture was washed six times with diethyl ether. Neutralization of the aqueous phase with 20% strength NaOH resulted in the precipitation of the title compound. The precipitate was filtered off and dried over P₂O₅ under reduced pressure. Purification was by recrystallization. The yield was 50%.

IR: 1/λ (cm⁻¹)=3059, 1587, 1498, 1220, 837, 814

¹H NMR (CDCl₃, ppm): 12.63 (bs, 1H), 8.74-8.72 (m, 2H), 7.27-7.17 (m, 4H), 7.0-6.90 (m, 2H), 4.08 (q, 2H, J=7.1 Hz), 1.21 (t, 3H, J=7.1 Hz)

Example 3A 4-(4-Fluorophenyl)-1-n-propyl-5-(4-pyridyl)-2-thioimidazole

The process of example 1 was employed, where step d) the 2-(4-fluorophenyl)-1-(4-pyridyl)-α-hydroxyiminoethanone was reacted with twice the equivalent amount of 1,3,5-tri-n-propylhexahydro-1,3,5-triazine.

The yield was in the range of 60-91%.

IR: 1/λ (cm⁻¹)=2932, 1586, 1500, 1221, 831, 814

¹H NMR (CDCl₃, ppm): 12.47 (bs, 1H), 8.76-8.73 (m, 2H), 7.26-7.13 (m, 4H), 7.0-6.96 (m, 2H), 3.98 (t, 2H, J=7.8 Hz), 1.65 (m, 2H), 0.82 (t, 3H, J=7.4 Hz)

Example 3B 4-(4-Fluorophenyl)-1-n-propyl-5-(4-pyridyl)-2-thioimidazole

Alternatively, to prepare the title compound, the process of example 2 was employed, where step a) 2-(4-fluorophenyl)-1-(4-pyridyl)-α-hydroxyiminoethanone was reacted with the equimolar amount of n-propylamine.

The yield was in the range of 32-72%.

Example 4 4-(4-Fluorophenyl)-1-isopropyl-5-(4-pyridyl-2-thioimidazole

To prepare the title compound, the process of example 2 was employed, where in step a) 2-(4-fluorophenyl)-1-(4-pyridyl)-α-hydroxyiminoethanone was reacted with the equimolar amount of isopropylamine.

IR: 1/λ (cm⁻¹)=3040, 1584, 1500, 1230, 841, 819

¹H NMR (CDCl₃, ppm): 11.73 (bs, 1H), 8.76-8.74 (m, 2H,), 7.28 (m, 2H), 7.17-7.10 (m, 2H), 7.0-6.92 (m, 2H), 4.89 (m, 1H), 1.48 (s, 3H), 1.45 (s, 3H)

Example 5 1-Cyclohexyl-4-(4-fluorophenyl)-5-(4-pyridyl)-2-thioimidazole

To prepare the title compound, the process of example 2 was used, where in step a) 2-(4-fluorophenyl)-1-(4-pyridyl)-α-hydroxyiminoethanone was reacted with the equimolar amount of cyclohexylamine.

IR: 1/λ (cm⁻¹)=2934, 1560, 1505, 1228, 842

¹H NMR (CDCl₃, ppm): 11.32 (bs, 1H), 8.76-8.73 (m, 2H), 7.30-7.31 (m, 2H), 7.15-7.08 (m, 2H), 7.01-6.92 (m, 2H), 4.60-4.25 (m, 1H), 2.0-1.18 (m, 10H)

Example 6 1-Cyclopropyl-4-(4-fluorophenyl)-5-(4-pyridyl)-2-thioimidazole

The same process as in example 1 was used, where in step d) the 2-(4-fluorophenyl)-1-(4-pyridyl)-α-hydroxyiminoethanone was reacted with twice the equivalent amount of 1,3,5-tricyclopropylhexahydro-1,3,5-triazine.

IR: 1/λ (cm⁻¹)=3013, 1589, 1515, 1499, 1487, 1223, 830, 685

1H NMR (CDCl₃, ppm): 12.76 (bs, 1H), 8.68-8.65 (m, 2H), 7.26-7.19 (m, 4H), 7.07-6.99 (m, 2H), 3.12-3.08 (m, 1H), 1.02-0.95 (m, 2H), 0.76-0.71 (m, 2H)

Example 7 4-(4-Fluorophenyl)-1-phenyl-5-(4-pyridyl)-2-thioimidazole

To prepare the title compound, the process of example 2 was employed, where in step a) 2-(4-fluorophenyl)-1-(4-pyridyl)-α-hydroxyiminoethanone was reacted with the equimolar amount of aniline.

IR: 1/λ (cm⁻¹)=2880, 1597, 1504, 1227, 844, 825

¹H NMR (CDCl₃, ppm): 11.58 (bs, 1H), 8.48-8.41 (m, 2H), 7.78-6.74 (m, 11H)

Example 8 1-Benzyl-4-(4-fluorophenyl)-5-(4-pyridyl)-2-thioimidazole

To prepare the title compound, the process of example 2 was employed, where in step a) 2-(4-fluorophenyl)-1-(4-pyridyl)-α-hydroxyiminoethanone was reacted with the equimolar amount of benzylamine.

IR: 1/λ (cm⁻¹)=3032, 1587, 1497, 1225, 1158, 837, 816

¹H NMR (CDCl3, ppm): 12.88 (bs, 1H), 8.56-8.53 (m, 2H), 7.27-6.90 (m, 11H), 5.28 (s, 2H)

Example 9 1-Dimethylaminophenyl-4-(4-fluorophenyl)-5-(4-pyridyl)-2-thioimidazole

To prepare the title compound, the process of example 2 was employed, where in step a) 2-(4-fluorophenyl)-1-(4-pyridyl)-α-hydroxyiminoethanone was reacted with the equimolar amount of 4-dimethylaminobenzylamine.

IR: 1/λ (cm⁻¹)=2891, 1606, 1500, 1357, 1225, 835, 816

¹H NMR (d₆-DMSO, ppm): 13.05 (bs, 1H), 8.43-8.41 (m, 2H), 7.37-7.03 (m, 8H), 6.98-6.60 (m, 2H), 2.89 (s, 6H)

Example 10 4-(4-Fluorophenyl)-1-(3-pyridyl)-5-(4-pyridyl)-2-thioimidazole

To prepare the title compound, the process of example 2 was employed, where in step a) 2-(4-fluorophenyl)-1-(4-pyridyl)-α-hydroxyiminoethanone was reacted with the equimolar amount of 3-pyridylamin.

IR: 1/λ (cm⁻¹)=3035, 1597, 1478, 1433, 1433, 1224, 813, 708

¹H NMR (d₆-DMSO, ppm): 13.34 (s, 1H), 8.54-8.45 (m, 4H), 7.76-7.75 (m, 1H), 7.40-7.13 (m, 7H)

Example 11 1-Dimethylaminoethyl-4-(4-fluorophenyl)-5-(4-pyridyl)-2-thioimidazole

The same process as in example 1 was used, where in step d) the 2-(4-fluoro-phenyl)-1-(4-pyridyl)-α-hydroxyiminoethanone was reacted with twice the equivalent amount of 1,3,5-tri(2-dimethylaminoethyl)hexahydro-1,3,5-triazine.

IR: 1/λ (cm⁻¹)=2772, 1597, 1503, 1225, 835, 815

¹H NMR (CDCl₃, ppm): 8.74-8.72 (m, 2H), 7.30-7.17 (m, 4H), 7.04-6.94 (m, 2H), 4.13 (t, 2H, J=6.8 Hz), 2.56 (t, 2H, J=6.7 Hz), 2.11 (s, 6H)

Example 12 4-(4-Fluorophenyl)-5-(4-pyridyl)-1-(2,2,6,6-tetramethylpiperidin-4-yl)-2-thioimidazole

The same process as in example 1 as employed, where in step d) the 2-(4-fluorophenyl)-1-(4-pyridyl)-α-hydroxyiminoethanone was reacted with twice the molar amount of 2,2,6,6-tetramethyl-4-methyleneaminopiperidine.

IR: 1/λ (cm⁻¹)=2964, 1587, 1498, 1352, 1234, 838, 815

Example 13 1-Dimethylaminopronyl-4-(4-fluorophenyl)-5-(4-pyridyl)-2-thioimidazole

The same process as in example 1 was employed, where in step d) the 2-(4-fluorophenyl)-1-(4-pyridyl)-α-hydroxyiminoethanone was [lacuna] with twice the equivalent amount of 1,3,5-tri(3-dimethylaminopropyl)hexahydro-1,3,5-triazine.

Example 14 4-(4-Fluorophenyl)-1-(3-N-morpholinopropyl)-5-(4-pyridyl)-2-thioimidazole

The same process as in example 1 was employed, where in step d) the 2-(4-fluorophenyl)-1-(4-pyridyl)-α-hydroxyiminoethanone was reacted with twice the equivalent amount of 1,3,5-tri(N-morpholinopropyl)hexahydro-1,3,5-triazine.

IR: 1/λ (cm⁻¹)=2847, 1502, 1233, 1114, 842, 817

¹H NMR (CDCl₃, ppm): 12.11 (bs, 1H), 8.75-8.71 (m, 2H), 7.26-7.18 (m, 4H), 7.05-6.95 (m, 2H), 4.15-4.07 (m, 2H), 3.61-3.57 (m, 4H), 2.32-2.23 (m, 6H), 1.86-1.75 (m,2H)

Example 15 4-(4-Fluorophenyl)-1-(4-methylsulfanylphenyl)-5-(4-pyridyl)-2-thio-imidazole

The same process as in example 1 was employed, where in step d) the 2-(4-fluorophenyl)-1-(4-pyridyl)-α-hydroxyiminoethanone was reacted with twice the equivalent amount of 1,3,5-tri(4-methylsulfanylphenyl)hexahydro-1,3,5-triazine.

IR: 1/λ (cm⁻¹)=2693, 1597, 1495, 1220, 844, 817

¹H NMR (CDCl₃, ppm): 12.43 (bs, 1H), 8.47-8.44 (m, 2H), 7.32-7.12 (m, 6H), 7.06-6.97 (m, 2H), 6.90-6.87 (m, 2H), 2.50 (s, 3H)

Example 16 4-(4-Fluorophenyl)-1-N-morpholinoethyl-5-(4-pyridyl)-2-thioimidazole

The same process as in example 1 was employed, where in step d) the 2-(4-fluorophenyl)-1-(4-pyridyl)-α-hydroxyiminoethanone was reacted with twice the equivalent amount of 1,3,5-tri(N-morpholinoethylhexahydro-1,3,5-triazine.

IR: 1/λ (cm⁻¹)=2813, 1599, 1508, 1232, 1117, 850, 835

¹H NMR (d₆-DMSO): 12.91 (bs, 1H), 8.71-8.68 (m, 2H), 7.49-7.46 (m, 2H), 7.25-7.16 (m, 4H), 4.04 (t, 2H, J=Hz), 2.40 (t, 2H, J=Hz), 2.16 (t, 4H, J=3.8 Hz)

Example 17 4-(4-Fluorophenyl)-1-(3-hydroxypronyl)-5-(4-pyridyl)-2-thioimidazole

The same process as in example 1 was employed, where in step d) the 2-(4-fluorophenyl)-1-(4-pyridyl)-α-hydroxyiminoethanone was reacted with twice the equivalent amount of 1,3,5-tri(3-hydroxypropylhexahydro-1,3,5-triazine.

IR: 1/λ (cm⁻¹)=3049, 2926, 1499, 1223, 1162, 1061, 838

¹H NMR (d₆-DMSO, ppm): 12.98 (s, 1H), 8.71-8.68 (m, 2H), 7.47-7.44 (m, 2H), 7.29-7.12(m, 4H), 4.47-4.43 (bs, 1H), 3.97 (t, 2H, J=7.4 Hz), 3.27 (t, 2H, J=6.2 Hz), 1.68-1.54 (m, 2H)

Example 18 1-(1-Benzylpiperidin-4-yl-4-(4-fluorophenyl)-5-(4-pyridyl)-2-thioimidazole

The same process as in example 1 was employed, where in step d) the 2-(4-fluorophenyl)-1-(4-pyridyl)-α-hydroxyiminoethanone was reacted with twice the molar amount of 1-benzyl-4-methyleneaminopiperidine.

IR: 1/λ (cm⁻¹)=2903, 1504, 1247, 1227, 853, 741

¹H NMR (d₆-DMSO): 12.93 (s, 1H), 8.73-8.70 (m, 2H), 7.50-7.47 (m, 2H), 7.29-7.11 (m, 9H), 3.96-4.12 (m, 1H), 3.38 (s, 2H), 3.85-3.75 (m, 2H), 2.31-2.18 (m, 2H), 1.93-1.64 (m, 4H)

Example 19 1-Allyl-4-(4-fluorophenyl)-5-(4-pyridyl)-2-thioimidazole

The same process as in example 1 was employed, where in step d) the 2-(4-fluorophenyl)-1-(4-pyridyl)-α-hydroxyiminoethanone was reacted with twice the equivalent amount of 1,3,5-tri(prop-2-en-1-yl)hexahydro-1,3,5-triazine.

IR: 1/λ (cm⁻¹)=2695, 1700, 1600, 1506, 1421, 1227, 1005, 934, 927, 841, 829, 817

¹ H NMR (CDCl₃, ppm): 12.49 (bs, 1H), 8.72-8.65 (m, 2H), 7.29-7.22 (m, 4H), 4H), 7.04-6.96 (m, 2H), 6.00-5.81 (m, 1H), 5.25-5.19 (m, 1H), 5.02-4.93 (m, 1H), 4.66-4.64 (m, 2H)

Example 20 4-(4-Fluorophenyl)-1-methyl-2-methylthio-5-(4-pyridylimidazole

a) The 1-substituted 4-(4-fluorophenyl)-5-(4-pyridyl)imidazole-2-thione (compound 5 from scheme 1) was prepared as described in example 1, the added imine compound being 1,3,5-trimethylhexahydro-1,3,5-triazine.

b) To methylate the sulfur, 0.7 g of the resulting thione compound (5) was then suspended under protective gas in 20 ml of dry ethanol, and the equimolar amount of dimethyl sulfate or methyl iodide was added. A spatula tip of Na₂CO₃ was added, and the reaction mixture was then heated under reflux for 3 h. After cooling, the inorganic salts were filtered off and the solvent was removed using a rotary evaporator. The crude product was purified by column chromatography.

The yield was 43%.

IR: 1/λ (cm⁻¹)=1603, 1510, 1220, 1160, 850, 830, 814

¹H NMR (CDCl₃, ppm): 8.70-8.67 (m, 2H), 7.43-7.36 (m, 2H), 7.24-7.22 (m, 2H), 6.98-6.89 (m, 2H), 3.47 (s, 3H), 2.72 (s, 3H)

Example 21 4-(4-Fluorophenyl)-2-methylthio-1-n-propyl-5-(4-pyridyl)imidazole

The title compound was prepared analogously to the process of example 20. 1,3,5-tri-n-propylhexahydro-1,3,5-triazine was used for cyclizing the imidazole compound.

IR: 1/λ (cm⁻¹)=2929, 1601, 1511, 1221, 849, 829, 816

¹H NMR (CDCl₃, ppm): 8.71-8.68 (m, 2H), 7.41-7.34 (m, 2H), 7.26-7.23 (m, 2H), 6.96-6.87 (m, 2H), 3.79 (t, 2H, J=7.7 Hz), 2.74 (s, 3H), 1.64-1.52 (m, 2H), 0.80 (t, 3H, J=7.4 Hz)

Example 22 1-Cyclopropyl-4-(4-fluorophenyl)-2-methylthio-5-(4-pyridyl)imidazole

The title compound was prepared analogously to the process of example 20. 1,3,5-tricyclopropylhexahydro-1,3,5-triazine was used for cyclizing the imidazole compound.

¹H NMR (CDCl₃, ppm): 8.64-8.61 (m, 2H), 7.41-7.34 (m, 2H), 7.27-7.24 (m, 2H, 6.98-6.90 (m, 2H), 3.13-3.02 (m, 1H), 2.74 (s, 3H), 0.95-0.91 (m, 2H), 0.70-0.66 (m, 2H)

Example 23 4-(4-Fluorophenyl)-2-methylthio-1-N-morpholinoethyl-5-(4-pyridyl)-imidazole

The title compound was prepared analogously to the process of example 20. 1,3,5-tri(N-morpholino)ethylhexahydro-1,3,5-triazinethanamine was used for cyclizing the imidazole compound.

IR: 1/λ (cm⁻¹)=2852, 1600, 1509, 1215, 1114, 871, 841, 813

¹H NMR (CDCl₃, ppm): 8.71-8.68 (m, 2H), 7.41-7.34 (m, 2H), 7.30 (m, 2H), 6.96-6.87 (m, 2H), 3.96 (t, 3H, J=7.0 Hz), 3.60 (t, 4H, J=4.6 Hz), 2.74 (s, 3H), 2.46 (t, 2H, J=7.0 Hz), 2.32 (t, 4H, J=4.7 Hz)

Example 24 4-(4-Fluorophenyl)-2-methylthio-1-N-morpholinopropyl-5-(4-pyridyl)-imidazole

The title compound was prepared analogously to the process of example 20. 1,3,5-tri(3-N-morpholinopropyl)hexahydro-1,3,5-triazine was used for cyclizing the imidazole compound.

IR: 1/λ (cm⁻¹ )=2814, 1509, 1219, 1114, 842

¹H NMR (CDCl₃, ppm): 8.71-8.68 (m, 2H), 7.41-7.36 (m, 2H), 7.27-7.23 (m, 2H), 6.96-6.87 (m, 2H), 3.98-90 (m, 2H), 3.64-3.59 (m, 4H), 2.74 (s, 3H), 2.27-2.19 (m 6H), 1.77-1.68 (2H)

Example 25 4-(4-Fluorophenyl)-2-methylthio-5-(4-pyridyl)-1-(2,2,6,6-tetramethyl-piperidin-4-yl)imidazole

The title compound was prepared analogously to the process of example 20. 2,2,6,6-tetramethyl-4-methylenaminopiperidine was used for cyclizing the imidazole compound.

IR: 1/λ (cm⁻¹)=2968, 1600, 1509, 1343, 1229, 1033, 835, 813

¹H NMR (CDCl₃, ppm): 8.73-8.70 (m, 2H), 7.37-7.22 (m, 4H), 6.94-6.86 (m, 2H), 4.41-4.28 (m, 1H), 2.75 (s, 3H), 2.05-2.04 (m, 2H), 1.74-1.66 (m, 2H), 1.16, 1.04 (2s, 12H)

Example 26 1-Benzylpiperidin-4-yl-4-(4-fluorophenyl)-2-methylthio-5-(4-pyridyl)-imidazole

The title compound was prepared analogously to the process of example 20. 1-benzyl-4-methylenaminopiperidine was used for cyclizing the imidazole compound.

IR: 1/λ (cm⁻¹)=2929, 2809, 1602, 1509, 1220, 1158, 840, 828, 814, 743, 701

¹H NMR (d₆-DMSO, ppm): 8.72-8.69 (m, 2H), 7.41-7.38 (m, 2H), 7.30-7.21 (m, 7H), 7.09-7.0 (m, 2H), 3.60-3.72 (m, 1H), 3.40 (s, 1H), 2.85-2.80 (m, 2H), 2.42-2.22 (m, 2H), 1.81-1.76 (m, 4H)

Example 27 1-Ethyl-4-(4-fluorophenyl)-2-(4-methylsulfonyl)benzylthio-5-(4-pyridyl)-imidazole

a) The 1-substituted 4-(4-fluorophenyl)-5-(4-pyridyl)imidazole-2-thione (compound 5 of scheme 2) was prepared as described in example 2, the added amine compound being ethylamine.

b) To benzylate the sulfur, 0.4 g of the resulting thione compound (5) was suspended under protective gas in 15 ml of dry ethanol, and the equimolar amount of 4-methyl-sulfonylbenzyl chloride was added. A spatula tip of Na₂CO₃ was added, and the reaction mixture was then heated under reflux for 5 h. After cooling, the Na₂CO₃ was filtered off and the solvent was removed using a rotary evaporator. The crude product of the title compound (compound 9 in scheme 3.2) was purified by column chromatography.

Yield: 55%

IR: 1/λ (cm⁻¹)=1510, 1304, 1149, 841, 766

¹H NMR (CDCl₃, ppm): 8.71-8.69 (m, 2H), 7.91-7.87 (m, 2H),7.62-7.58 (m, 2H), 7.41-7.34 (m, 2H), 7.26-7.21 (m, 2H), 6.98-6.91 (m, 2H), 4.52 (s, 2H), 3.73 (q, 2H, J=7.21 Hz), 3.05 (s, 3H), 1.07 (t, 3H, J=7.2 Hz)

Example 28 2-Benzylthio-4-(4-fluorophenyl)-1-n-propyl-5-(4-pyridyl)imidazole

a) The 1-substituted 4-(4-fluorophenyl)-5-(4-pyridyl)imidazole-2-thione (compound 5 of scheme 1) was prepared as described in example 1, the added imine compound being 1,3,5-tri-n-propylhexahydro-1,3,5-triazine.

b) The sulfur was benzylated using benzyl chloride, following the process of example 27 (step b).

IR: 1/λ (cm⁻¹)=1602, 1510, 1220, 851, 833, 815, 695

¹H NMR (CDCl3, ppm): 8.70-8.67 (m, 2H), 7.43-7.26 (m, 6H), 7.19-7.16 (m, 2H), 6.98-6.89 (m, 2H), 4.39 (s, 2H), 3.56 (t, 2H, J=7.6 Hz), 1.42-1.30 (m, 2H), 0.66 (t, 3H, J=7.4 Hz)

Example 29 2-(4-Chlorobenzyl)thio-4-(4-fluorophenyl)-1-n-propyl-5-(4-pyridyl)-imidazole

The title compound was prepared as described in example 28, except that 4-chlorobenzyl chloride was used for the benzylation.

IR: 1/λ (cm⁻¹)=2972, 1602, 1509, 1343, 1222, 1092, 844, 828, 816, 743, 698

¹H NMR (CDCl₃, ppm): 8.71-8.68 (m, 2H), 7.41-7.34 (m, 2H), 7.27-7.26 (m, 4H), 7.19-7.16 (m, 2H), 6.98-6.89 (m, 2H), 4.38 (s, 2H), 3.61 (t, 2H, J=7.6 Hz), 1.45-1.33 (m, 2H), 0.68 (t, 3H, 7.4 Hz)

Example 30 4-(4-Fluorophenyl)-2-(4-methylbenzyl)thio-1-n-propyl-5-(4-pyridyl)-imidazole

The title compound was prepared as described in example 28, except that 4-methylbenzyl chloride was used for the benzylation.

IR: 1/λ (cm⁻¹)=2927, 1603, 1510, 1222, 849, 831, 815

¹H NMR (CDCl₃, ppm): 8.70-8.67 (m, 2H), 7.43-7.36 (m, 2H), 7.23-7.09 (m, 6H), 6.98-6.89 (m, 2H), 4.37 (s, 2H), 3.59 (t, 2H, J=7.7 Hz), 2.34 (s, 3H), 1.44-1.33 (m, 2H), 0.67 (t, 3H, J=7.4 Hz)

Example 31 4-(4-Fluorophenyl)-2-(4-methylthio)benzylthio-1-n-propyl-5-(4-pyridyl)-imidazole

The title compound was prepared by the process of example 27, with n-propylamine being in step (a) and 4-methylthiobenzyl chloride being used in step (b) for the benzylation.

IR: 1/λ (cm⁻¹)=2922, 1602, 1508, 1405, 1222, 848, 814

¹H NMR (CDCl₃, ppm): 8.70-8.67 (m, 2H), 7.42-7.35 (m, 2H), 7.24-7.15 (m, 6H), 6.98-6.89 (m, 2H), 4.37 (s, 2H), 3.60 (t, 2H, J=7.6 Hz), 2.48 (s, 3H), 1.44-1.33 (m, 2H), 0.68 (t, 3H, J=7.4 Hz)

Example 32 4-(4-Fluorophenyl)-2-(4-methylsulfinyl)benzylthio-1-n-propyl-5-(4-pyridyl)imidazole

The process of example 31 was repeated, except that in step (b) 4-methylsulfinyl-benzyl chloride was used for the benzylation.

IR: 1/λ (cm⁻¹)=2959, 1602, 1509, 1407, 1221, 1089, 1048, 842, 816

¹H NMR (CDCl₃, ppm): 8.71-8.68 (m, 2H), 7.63-7.51 (m, 4H), 7.41-7.34 (m, 2H), 7.21-7.18 (m, 2H), 6.98-6.90 (m, 2H), 4.48 (s, 2H), 3.64 (t, 2H, J=7.6 Hz), 2.72 (s, 3H), 1.42-1.35 (m, 2H), 0.69 (t, 3H, J=7.4 Hz)

Example 33 4-(4-Fluorophenyl)-2-(4-methylsulfonyl)benzylthio-1-n-propyl-5-(4-pyridyl)imidazole

The process of example 31 was repeated, except that in step (b) 4-methylsulfonylbenzyl chloride was used for the benzylation.

IR: 1/λ (cm⁻¹)=1509, 1306, 1219, 1150, 964, 844, 768, 744

¹H NMR (CDCl₃, ppm): 8.70-8.68 (m, 2H), 7.91-7.87 (m, 2H), 7.62-7.58 (m, 2H), 7.41-7.26 (m, 4H), 7.0-6.92 (m, 2H), 4.55 (s, 2H), 3.66 (t, 2H, J=7.6 Hz), 3.05 (s, 3H), 1.48-1.37 (m, 2H), 0.71 (t, 3H, J=7.5 Hz)

Example 34 2-(4-Chlorobenzyl)thio-4-(4-fluorophenyl)-1-isopropyl-5-(4-pyridyl)-imidazole

The title compound was prepared by the process of example 27, where isopropylamine was used in step (a) and 4-chlorobenzyl chloride was used in step (b) for the benzylation.

IR: 1/λ (cm⁻¹)=1509, 1222, 1092, 850, 815

¹H NMR (CDCl₃, ppm): 8.73-8.71 (m, 2H), 7.38-7.21 (m, 8H), 6.97-6.88 (m, 2H), 4.49 (s, 2H), 4.27-4.20 (m, 1H), 1.38 (s, 3H), 1.27 (s, 3H)

Example 35 4-(4-Fluorophenyl)-2-(4-methylsulfonyl)benzylthio-1-isopropyl-5-(4-pyridyl)imidazole

The title compound was prepared by the process from example 27, where isopropylamine was used in step (a) and 4-methylsulfonylbenzyl chloride was used in step (b) for the benzylation.

IR: 1/λ (cm⁻¹)=1510, 1306, 1219, 1149, 843, 766, 744

¹H NMR (CDCl₃, ppm): 8.72-8.69 (m, 2H), 7.92-7.88 (m, 2H), 7.67-7.62 (m, 2H), 7.35-7.21 (m, 4H), 4.60 (s, 2H), 4.25-4.18 (m, 1H), 3.05 (s, 3H), 1.39, 1.35 (2s, 6H)

Example 36 1-Cyclopropyl-4-(4-fluorophenyl)-2-(1-phenylpropynyl)thio-5-(4-pyridyl)-imidazole

The title compound was prepared by the process of example 28, where 1,3,5-tricyclopropylhexahydro-1,3,5-triazine was used in step (a) and 1-phenylprop-1-ynyl chloride was used in step (b) for the benzylation.

IR: 1/λ (cm⁻¹)=1603, 1509, 1388, 1221, 842, 816, 753, 688

¹H NMR (CDCl₃, ppm): 8.64-8.61 (m, 2H), 7.44-7.22 (m, 9H), 6.99-6.91 (m, 2H), 4.31 (s, 2H), 3.18-3.11 (m, 1H), 0.97-0.90 (m, 2H), 0.75-0.69 (m, 2H)

Example 37 1-Cyclopropyl-4-(4-fluorophenyl)-2-(1-(4-chloro)phenylpropenyl)thio-5-(4-pyridyl)imidazole

The procedure of example 36 was adopted, except that in step (b) 1-(4-chloro-phenyl)prop-1-enyl chloride was used for the benzylation.

¹H NMR (CDCl₃, ppm): 8.64-8.61 (m, 2H), 7.42-7.35 (m, 2H), 7.29-7.26 (m, 4H), 7.23-7.20 (m, 2H), 7.0-6.91 (m, 2H), 6.60 (d, 1H, J=15.7 Hz), 6.48-6.37 (m, 1H), 4.11 (d, 2H, J=6.5 Hz), 3.12-3.0 (m, 1H), 0.94-0.90 (m, 2H), 0.68-0.64 (m,2H)

Example 38 1-Cyclopropyl-4-phenyl-2-(1-(4-fluorophenylpropenyl)thio-5-(4-pyridyl)-imidazole

The procedure of example 36 was adopted, except that in step (b) 1-phenylprop-1-enyl chloride was used for the benzylation.

IR: 1/λ (cm⁻¹)=3025, 1599, 1509, 1384, 1219, 963, 838, 824, 815, 750, 692

¹H NMR (CDCl₃, ppm): 8.64-8.61 (m, 2H), 7.44-7.28 (m, 7H), 7.23-7.20(m, 2H), 7.02-6.92 (m, 2H), 6.65 (d, 2H, J=15.8 Hz), 6.51-6.40 (m, 1H), 4.13 (d, 2H, J=6.7 Hz), 3.11-3.04 (m, 1H), 0.95-0.88 (m, 2H), 0.71-0.65 (m, 2H)

Example 39 1-Cyclohexyl-4-(4-fluorophenyl)-2-(4-methylsulfonyl)benzylthio-5-(4-pyridyl)imidazole

The title compound was prepared by the process of example 27 where cyclo-hexylamine was used in step (a) and 4-methylsulfonylbenzyl chloride was used in step (b) for the benzylation.

IR: 1/λ (cm⁻¹)=2930, 1599, 1509, 1304, 1149, 838, 763

¹H NMR (CDCl₃, ppm): 8.73-8.70 (m, 2H), 7.92-7.88 (m, 2H), 7.67-7.63 (m, 2H), 7.34-7.21 (m, 4H), 6.97-6.88 (m, 2H), 4.64 (s, 2H), 3.73-3.71 (m, 1H), 2.10-1.62 (m, 10H)

Example 40 4-(4-Fluorophenyl)-2-(4-methylsulfonyl)benzylthio-1-phenyl-5-(4-pyridyl)imidazole

The procedure of example 39 was adopted, except that the amine in step (a) was aniline.

IR: 1/λ (cm⁻¹)=1598, 1510, 1408, 1303, 1149, 1090, 840, 765, 694

¹H NMR (CDCl₃, ppm): 8.41-8.38 (m, 2H), 7.89-7.85 (m, 2H), 7.61-7.38 (m, 7H), 7.07-6.92 (m, 6H), 4.50 (s, 2H), 3.04 (s, 3H)

Example 41 1-Benzyl-4-(4-fluorophenyl)-2-(4-methylsulfonyl)benzylthio-5-(4-pyridyl)-imidazole

The procedure of example 39 was adopted, except that the imine used in step (a) was benzylamine.

IR: 1/λ (cm⁻¹)=1600, 1509, 1304, 1220, 1147, 1090, 843, 767, 725

¹H NMR (CDCl₃, ppm): 8.57-8.54 (m, 2H), 7.90-7.85 (m, 2H), 7.58-7.54 (m, 2H), 7.45-7.38 (m, 2H), 7.26-7.23 (m, 3H), 7.08-6.97 (m, 4H), 6.80-6.79 (m, 2H), 4.93 (s, 2H), 4.47 (s, 2H), 3.05 (s, 3H)

Example 42 2-Benzylthio-4-(4-fluorophenyl)-1-N-morpholinoethyl-5-(4-pyridyl)-imidazole

The title compound was prepared by the process of example 27, where N-morpholinoethylamine was used in step (a) and benzyl chloride was used in step (b) for the benzylation.

IR: 1/λ (cm⁻¹)=2802, 1603, 1510, 1219, 1116, 870, 836, 814, 712, 695

¹H NMR (CDCl₃, ppm): 8.71-8.68 (m, 2H), 7.44-7.37 (m, 2H), 7.30-7.26 (m, 5H), 7.26-7.19 (m, 2H), 6.99-6.90 (m, 2H), 4.37 (s, 2H), 3.80-3.54 (m, 6H), 2.24-2.17 (m, 6H)

Example 43 2-Benzylthio-4-(4-fluorophenyl)-1-N-morpholinopropyl-5-(4-pyridyl-imidazole

Example 28 was repeated, except that the added imine compound in step (a) was 1,3,5-tri(3-N-morpholinopropyl)hexahydro-1,3,5-triazine.

IR: 1/λ (cm⁻¹)=2814, 1602, 1509, 1460, 1218, 1114, 970, 842, 812, 696

¹H NMR (CDCl₃, ppm): 8.70-8.67 (m, 2H), 7.43-7.26 (m, 7H), 7.20-7.17 (m, 2H), 6.98-6.89 (m, 2H), 4.39 (s, 2H), 3.74-3.56 (m, 6H), 2.19-2.06 (m, 6H), 1.55-1.36 (m, 2H)

Example 44 4-(4-Fluorophenyl)-2-(4-methylsulfonyl)benzylthio-1-N-morpholinoethyl-5-(4-pyridyl)imidazole

The title compound was prepared by the process of example 28, where 1,3,5-tri(3-N-morpholinopropyl)hexahydro-1,3,5-triazine was used in step (a) and 4-methyl-sulfonylbenzyl chloride was used in step (b) for the benzylation.

IR: 1/λ (cm⁻¹)=2924, 1600, 1510, 1302, 1147, 1115, 839, 765

¹H NMR (CDCl₃, ppm): 8.71-8.68 (m, 2H), 7.91-7.87 (m, 2H), 7.59-7.55 (m, 2H), 7.40-7.33 (m, 2H), 7.22-7.19 (m, 2H), 6.99-6.90 (m, 2H), 4.49 (s, 2H), 3.77 (t, 2H, J=5.7 Hz), 3.63-3.58 (m, 4H), 3.06 (s, 3H), 2.23-2.15 (m, 6H), 1.60-1.41 (m, 2H)

Example 45 4-(4-Fluorophenyl)-2-(4-methylsulfinyl)benzylthio-1-N-morpholinoethyl-5-(4-pyridyl)imidazole

The title compound was prepared by the process of example 28, where 1,3,5-tri(3-N-morpholinopropyl)hexahydro-1,3,5-triazine was used in step (a) and 4-methylsulfinyl-benzyl chloride was used in step (b) for the benzylation.

IR: 1/λ (cm⁻¹)=2956, 1601, 1509, 1406, 1220, 1115, 1047, 837, 815

¹H NMR (CDCl₃, ppm): 8.71-8.68 (m, 2H), 7.63-7.50 (m, 4H), 7.41-7.34 (m, 2H), 7.22-7.19 (m, 2H), 6.98-90 (m, 2H), 4.47 (s, 2H), 3.78 (t, 2H, J=7.8 Hz), 3.60-3.56 (m, 4H), 2.73 (s, 3H), 2.20-2.09 (m, 6H), 1.60-1.42 (m, 2H)

Example 46 2-Benzylthio-4-(4-fluorophenyl)-1-(2,2,6,6-tetramethylpiperidin-4-yl)-imidazole

The title compound was prepared by the process of example 28, where 2,2,6,6-tetra-methyl-4-methylenaminopiperidine was used in step (a) and benzyl chloride was used in step (b) for the benzylation.

IR: 1/λ (cm⁻¹)=2739, 1602, 1510, 1390, 1354, 1224, 1158, 840, 700

Example 47 4-(4-Fluorophenyl)-1-methyl-2-N-morpholinoethylthio-5-(4-pyridyl-imidazole

a) The 1-substituted 4-(4-fluorophenyl)-5-(4-pyridyl)imidazole-2-thione (compound 5 of scheme 1) was prepared as described in example 1, the added imine compound being 1,3,5-trimethylhexahydro-1,3,5-triazine.

b) To substitute the sulfur, 0.4 g of the resulting thione compound (5) was then suspended under protective gas in 20 ml of dry ethanol, and the equimolar amount of N-(2-chloroethyl)morpholine hydrochloride was added. A spatula tip of Na₂CO₃ and a spatula tip of NaI were added, and the reaction mixture was then heated under reflux for 5 h. After cooling, the salts were filtered off and the solvent was removed using a rotary evaporator. The crude product of the title compound (compound 10 of scheme 3) was purified by column chromatography.

Yield: 72%

IR: 1/λ (cm⁻¹)=2930, 2806, 1602, 1508, 1218, 1131, 1113, 1072, 1007, 865, 850, 829, 814

¹H NMR (CDCl₃, ppm): 8.70-8.67 (m, 2H), 7.41-7.34 (m, 2H), 7.26-7.21 (m, 2H), 6.97-6.88 (m, 2H), 3.69 (t, 4H, J=4.6 Hz), 3.50 (s, 3H), 3.39 (t, 3H, J=6.9 Hz), 2.79 (t, 2H, J=7.0 Hz), 2.52 (t, 4H, J=4.6 Hz)

Example 48 1-cis-Phenylethenylthio-4-(4-fluorophenyl)-1-methyl-5-(4-pyridyl)-imidazole

a) The 1-substituted 4-(4-fluorophenyl)-5-(4-pyridyl)imidazole-2-thione (compound 5 of scheme 1) was prepared as described in example 1, the added imine compound being 1,3,5-trimethylhexahydro-1,3,5-triazine.

b) Dry ethanol was then added dropwise to an initial charge of 0.1 g of metallic sodium. 1.2 g of the compound (5) from step (a) were added, and a tenfold excess of phenylacetylene was then added. The reaction mixture was heated under reflux for 6 h. After cooling, the mixture was poured onto ice and extracted three times with petroleum ether. The organic phases were combined. When the organic phase was concentrated on a rotary evaporator, the title compound (compound 11 of scheme 3) precipitated out.

Yield: 27%

IR: 1/λ (cm⁻¹)=3380, 1600, 1513, 1226, 842

¹H NMR (CDCl₃, ppm): 8.72-8.69 (m, 2H), 7.52-7.23 (m, 9H), 6.99-6.90 (m, 3H), 6.74 (d, 1H, J=10.6 Hz), 3.52 (s, 3H)

Example 49 1-cis-Phenylethenylthio-4-(4-fluorophenyl)-1-n-propyl-5-(4-pyridyl)-imidazole

The title compound was prepared analogously to example 48, the imine added in step (a) being 1,3,5-tri-n-propylhexahydro-1,3,5-triazine.

IR: 1/λ (cm⁻¹)=1596, 1217, 835, 776, 682

¹H NMR (CDCl₃, ppm): 8.74-8.71 (m, 2H), 7.49-7.25 (m, 9H), 7.02-6.89 (m, 3H), 6.73 (d, 1H, J=10.7 Hz), 3.86 (t, 2H, J=7.7 Hz), 1.66-1.51 (m, 2H), 0.78 (t, 3H, J=7.4 Hz)

Example 50 2-cis-Phenylethenylthio-1-cyclopropyl-4-(4-fluorophenyl)-5-(4-pyridyl)-imidazole

The title compound was prepared analogously to example 48, the imine added in step (a) being 1,3,5-tricyclopropylhexahydro-1,3,5-triazine.

IR: 1/λ (cm⁻¹)=1596, 1509, 1385, 1217, 832, 785, 686

¹H NMR (CDCl₃, ppm): 8.67-8.64 (m, 2H), 7.54-7.26 (m, 10H), 7.0-6.92 (m, 2H), 6.76 (d, 1H, J=10.8 Hz), 3.17-3.13 (m, 1H), 1.0-0.96 (m, 2H), 0.72-0.68 (m, 2H)

Example 51 2-(1,2-Dibromo-2-phenylethyl)thio-4-(4-fluorophenyl)-1-n-propyl-5-(4-pyridyl)imidazole

To prepare the title compound, 0.4 g of the product of example 49 (compound 11 of scheme 3) was dissolved in CH₂Cl₂ and the equimolar amount of bromine in 15 ml of CH₂Cl₂ was slowly added dropwise. The reaction mixture was stirred at room temperature for 5 h and then washed repeatedly with aqueous sodium thiosulfate solution. The organic phase was dried over Na₂SO₄, the drying agent was filtered off and the solvent was removed using a rotary evaporator.

Yield: 98%

IR: 1/λ (cm⁻¹)=2963, 1631, 1603, 1513, 1224, 1158, 840, 815, 697

¹H NMR (CDCl₃, ppm): 8.74-8.72 (m, 2H), 7.59-7.25 (m, 9H), 6.99-6.90 (m, 2H), 6.21 (d, 1H, J=7.2 Hz), 5.74 (d, 1H, J=7.1 Hz), 3.89-3.85 (m, 2H), 1.55-1.51 (m, 2H), 0.77 (t, 3H, J=7.3 Hz)

Bisaryl Thioether

Example 52 4-(4-Fluorophenyl)-2-phenylthio-1-n-propyl-5-(4-pyridyl)imidazole

2-Chloro-1-n-propyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole (compound 7 of scheme 4) was prepared analogously to the process described in example 2, the amine used being, as in example 3B, n-propylamine.

b) The resulting imidazole compound (7) was then converted into the bisaryl thioether. To this end, NaH (2 eq.) was suspended in 10 ml of dry DMF and thiophenol (2 eq.) was slowly added dropwise. The reaction mixture was stirred at room temperature for 45 min, and 0.3 g of (4) was then added. The mixture was heated under reflux for 5.5 h. After cooling, distilled water was added to the mixture, the pH was adjusted to 1 using concentrated HCl and the mixture was washed six times with diethyl ether. When the mixture was neutralized using 20% strength NaOH the title compound (compound 12 of scheme 4) precipitated out. The precipitate was filtered off and dried over P₂O₅ under reduced pressure.

Yield: 70%

IR: 1/λ (cm⁻¹)=1509, 1226, 847, 729, 685

¹H NMR (CDCl₃, ppm): 8.75-8.72 (m, 2H), 7.45-7.26 (m, 9H), 6.98-6.89 (m, 2H), 3.95-3.87 (m, 2H), 1.49-1.34 (m, 2H), 0.71 (t, 3H, J=7.4 Hz)

Example 53 2-(4-Chlorophenyl)thio-4-(4-fluorophenyl)-1-n-propyl-5-(4-pyridyl)-imidazole

The same process as in example 52 was carried out, except that in step (b) 4-chlorothiophenol was used.

IR: 1/λ (cm⁻¹)=2958, 1601, 1511, 1473, 1226, 1090, 1013, 854, 824

¹H NMR (d₆-DMSO, ppm): 8.74-8.71 (m, 2H), 7.49-7.32 (m, 8H), 7.14-7.05 (m, 2H), 3.92 (t, 2H, J=7.5 Hz), 1.37-1.26 (m, 2H), 0.59 (t, 3H, J=7.4 Hz)

Example 54 4-(4-Fluorophenyl)-2-(4-methylsulfanyl)phenylsulfanyl-1-n-propyl-5-(4-pyridyl)imidazole

The same process as in example 52 was carried out, except that in step (b) 4-methylsulfanylthiophenol was used.

IR: 1/λ (cm⁻¹)=2961, 1602, 1510, 1478, 1226, 1103, 851, 796

¹H NMR (CDCl₃, ppm): 8.74-8.71 (m, 2H), 7.43-7.17 (m, 8H), 6.97-6.88 (m, 2H), 3.90 (t, 2H, J=7.7 Hz), 2.47 (s, 3H), 1.50-1.38 (m, 2H), 0.72 (t, 3H, J=7.4 Hz)

Example 55 4-(4-Fluorophenyl)-2-[(4-methylsulfinyl)phenyl]thio-1-n-propyl-5-(4-pyridyl)imidazole

0.4 g of the product of example 54 was dissolved in 10 ml of CH₂Cl₂ and 0.9 equivalent of m-chloroperbenzoic acid was added. The mixture was stirred at room temperature for 3 h. The resulting precipitate was filtered off and purified by column chromatography.

Yield: 73%

IR: 1/λ (cm⁻¹)=1602, 1510, 1226, 1056, 814, 699

¹H NMR (CDCl₃, ppm): 8.77-8.74 (m, 2H), 7.61-7.57 (m 2H), 7.46-7.37 (m, 4H), 7.30-7.28 (m, 2H), 6.98-6.90 (m, 2H), 3.92 (t, 2H, J=7.7 Hz), 2.72 (s, 3H), 1.49-1.45 (m, 2H), 0.72 (t, 3H, 7.4 Hz)

Example 56 4-(4-Fluorophenyl)-2-[(4-methylsulfonyl)phenyl]thio-1-n-propyl-5-(4-pyridyl)imidazole

0.4 g of the product of example 54 was dissolved in 10 ml of CH₂Cl₂ and 2.5 equivalents of m-chloroperbenzoic acid was added. The mixture was heated under reflux for 3 h. The resulting precipitate was filtered off and purified by column chromatography.

Yield: 67%

IR: 1/λ (cm⁻¹)=2967, 1604, 1510, 1316, 1226, 1153, 1094, 1078, 954, 815, 771

¹H NMR (CDCl₃, ppm): 8.79-8.76 (m, 2H), 7.88-7.83 (m, 2H), 7.45-7.27 (m, 6H), 6.99-6.90 (m, 2H), 3.92 (t, 2H, J=7.7 Hz), 3.04 (s, 3H), 1.50-1.43 (m, 2H), 0.73 (t, 3H, 7.4 Hz)

4-Methylimidazolethiols

Example 57 1-(4-Fluorophenyl)-4-methyl-5-(4-pyridyl)imidazole-2-thiol

The title compound was prepared analogously to example 1 from the corresponding α-hydroxyiminoethanone (compound 17 of scheme 6).

IR: 1/λ (cm⁻¹)=3039, 1591, 1516, 1372, 849, 823, 780

¹H NMR (d₆-DMSO, ppm): 12.76 (bs, 1H), 8.47-8.44 (m, 2H), 7.28-7.24 (m, 4H), 7.03-7.0 (m, 2H), 2.19 (s, 3H)

Example 58 4-(4-Fluorophenyl)-5-methyl-1-(3-pyridyl)imidazole-2-thiol

The title compound was prepared analogously to example 2 from the corresponding α-hydroxyiminoethanone (compound 19 of scheme 6).

IR: 1/λ (cm⁻¹)=3035, 1515, 1482, 1430, 1367, 1227, 844, 815, 711

¹H NMR (d₆-DMSO, ppm): 12.67 (bs, 1H), 8.50-8.49 (m, 1H), 8.48-8.47 (m, 1H), 7.69-7.65 (m, 1H), 7.45-7.41 (m, 1H), 7.16-7.12 (m, 4H), 2.08 (s, 3H)

Regioisomeric Thiols

Example 59 5-(4-Fluorophenyl)-1-n-propyl)-4-(4-pyridyl)imidazole-2-thiol

a) 1-(4-Fluorophenyl)-2-(4-pyridyl)-α-hydroxyiminoethanone

2.2 g (0.01 mol) of 1-(4-fluorophenyl)-2-(4-pyridyl)ethanone (compound 13 of scheme 5) were dissolved in 10 ml of glacial acetic acid. A solution of 0.7 g (0.01 mol) of NaNO₂ in 1 ml of water was slowly added dropwise to the initial charge, and the reaction mixture was stirred at room temperature for 2 h. 50 ml of distilled water were added and stirring was continued for 1 h. The precipitated compound (14), 1-(4-fluorophenyl)-2-(4-pyridyl)-α-hydroxyiminoethanone, was filtered off, washed with distilled water and dried over P₂O₅ under reduced pressure.

Yield: 2.0 g (80%)

b) 4-(4-Fluorophenyl)-1-methyl-5-(4-pyridyl)imidazole-2-thione

0.5 g of compound (14) was, together with twice the equivalent amount of 1,3,5-trimethylhexahydro-1,3,5-triazine, dissolved in 20 ml of dry ethanol and heated under reflux for 24 h. After cooling, the solvent was removed using a rotary evaporator. The residue was taken up in 20 ml of CHCl₃, cooled in an ice-bath, and 2,2,4,4-tetramethyl-3-thionocyclobutanone was slowly added with stirring. The ice-bath was removed and stirring was continued at room temperature for 1 h. The solvent was removed using a rotary evaporator and the resulting oily residue was solidified by addition of diethyl ether. The precipitate (15) was filtered off and purified by recrystallization.

Yield: 15%

IR: 1/λ (cm⁻¹)=2727, 1604, 1397, 1223, 833, 817

¹H NMR (CDCl₃, ppm): 12.03 (bs, 1H), 8.50-8.47 (m, 2H), 7.39-7.20 (m, 4H), 7.10-7.07 (m, 2H), 3.93-3.85 (m, 2H), 1.72-1.56 (m, 2H), 0.82 (t, 3H, J=7.4 Hz)

Example 60 5-(4-Fluorophenyl)-1-N-morpholinoethyl-4-(4-pyridyl)imidazole-2-thiol

The procedure of example 59 was adopted, except that the imine in step (b) was N-methylene-(N-morpholino)ethanamine.

IR: 1/λ (cm⁻¹)=2803, 1605, 1220, 1118, 849, 833

¹H NMR (d₆-DMSO): 13.09 (bs, 1H), 8.44-8.41 (m, 2H), 7.63-7.56 (m, 2H), 7.47-7.38 (m, 2H), 7.14-7.11 (m, 2H), 3.93 (t, 2H, J=6.8 Hz ), 3.44 (t, 4H, J=4.5 Hz), 2.42 (t, 2H), J=6.8 Hz), 2.14 (t, 4H, J=4.4 Hz)

Examples 61 to 65

(The compound numbers refer to scheme 8)

a) 2-Acetamido-4-methylpyridine (25)

100 mg of 4-dimethylaminopyridine are added to 200.0 g of 2-aminopicoline and 400 ml of acetic anhydride, and the mixture is refluxed for 5 h. After cooling, most of the excess acetic anhydride is distilled off, the residue is poured onto ice and the mixture is neutralized using aqueous ammonia solution. The resulting precipitate (25) is filtered off and dried under reduced pressure over P₂O₅.

Yield: 209.0 g (75%)

b) 2-Acetamidopyridine-4-carboxylic acid (26)

With stirring, 214.0 g of (25) are introduced a little at a time into an aqueous solution (temperature 50° C.) of 160 g of potassium permanganate. A further 360 g of potassium permanganate are added a little at a time over a period of one hour. Here, the temperature of the reaction mixture should not exceed 90° C. The mixture is stirred for another 1.5 h and then filtered hot, and the filtrate is adjusted to pH 3-4 using conc. HCl. The resulting white precipitate (26) is filtered off and dried under reduced pressure over P₂O₅.

Yield: 108.0 g (42%)

c) 2-Cyano-2-(4-fluorophenyl-1-(2-acetamido-4-pyridyl)ethanone (27)

18.0 g of (26) are taken up in 50 ml of abs. dimethylformamide (DMF), 17.0 g of carbonyldiimidazole (CDI) are added and the mixture is stirred at room temperature for 45 min. 14.9 g of 4-fluoroacetonitrile and 14.6 g of potassium tert-butoxide are then added, and the reaction mixture is heated at 120° C. for 2 h. After cooling, the mixture is stirred at room temperature overnight. Ice is then added to the solution, and the mixture is neutralized using conc. HCl. The resulting precipitate (27) is filtered off and dried under reduced pressure over P₂O₅.

Yield: 18.1 g (65%)

d) 2-(4-Fluorophenyl)-1-(2-amino-4-pyridyl)ethanone (28)

150 ml of 48% strength hydrobromic acid are added to 27.9 g of (27), and the reaction mixture is boiled gently for 30 h. After cooling, the mixture is poured onto ice and neutralized with concentrated ammonia. The resulting precipitate (28) is sucked dry, washed repeatedly with petroleum ether and cold diethyl ether and dried.

Yield: 11.7 g (55%)

e) 2-(4-Fluorophenyl)-1-(2-acetamido-4-pyridyl)ethanone (29)

12.0 g of the compound (28) are suspended in 100 ml of acetic anhydride, a spatula tip of 4-dimethylaminopyridine is added and the reaction mixture is heated under reflux for 5 h. Most of the excess acetic anhydride is distilled off, the residue is hydrolyzed and the mixture is adjusted to pH 7 using conc. ammonia. The resulting clear precipitate (29) is filtered off and dried under reduced pressure over P₂O₅.

Yield: 13.5 g (94%)

f) 2-(4-Fluorophenyl-1-(2-acetamido-4-pyridyl)-α-hydroxyiminoethanone (3)

30 ml of methanol are added to 2.1 g of sodium methoxide solution (30% in methanol), and this mixture is added to a solution of 1.2 g of isoamyl nitrite in 20 ml of methanol. With stirring, 3.0 g of (29) are added a little at a time, and the mixture is then stirred at room temperature for another 2 h. The solvent is distilled off, the solid residue is taken up in water and the pH is adjusted to 7 using 10% strength HCl. The resulting clear precipitate (30) is filtered off and dried under reduced pressure over P₂O₅.

Yield: 1.8 g (54%)

g) Preparation of the compounds (31):

(30) is, together with twice the amount of the appropriate triazine, dissolved in absolute ethanol and refluxed until the starting material has been completely converted. After cooling, the ethanol is removed using a rotary evaporator. The slightly oily residue solidifies on addition of diethyl ether. The precipitate of compounds 31 is filtered off and dried under reduced pressure.

Yields: R1=—CH₃: 74%

-   -   R1=—C₃H₇: 62%     -   R1=2,2,6,6-tetramethylpiperidin-4-yl: 81%     -   R1=N-morpholinopropyl-: 72%     -   R1=3-hydroxypropyl-: 56%         h) Preparation of the compounds (32)

Compound (31) is dissolved in CHCl₃ and the reaction mixture is cooled in an ice-bath. An equimolar solution of 2,2,4,4-tetramethylcyclobutane-3-thioxobutanone in CHCl₃ is slowly added dropwise to the initial charge, and the mixture is then stirred in the ice-bath for 30 min. The ice-bath is removed and stirring is continued at room temperature for 1 h. The solvent is then removed using a rotary evaporator and the solid residue is triturated in diethyl ether. The precipitate (32) is filtered off and dried under reduced pressure.

Yields: R1=—CH₃: 96%

-   -   R1=—C₃H₇: 74%     -   R1=2,2,6,6-tetramethylpiperidin-4-yl: 61%     -   R1=N-morpholinopropyl-: 82%     -   R1=3-hydroxypropyl-: 71%         i) Preparation of the Compounds (33)

Under protective gas, compound (32) is suspended in abs. ethanol, and an equimolar amount of methyl iodide is added. A spatula tip of Na₂CO₃ is added and the reaction mixture is refluxed until the starting material has been completely converted. After cooling, the inorganic salts are filtered off and the solvent is removed using a rotary evaporator. The crude product (33) is purified by column chromatography.

Example 61 4-(4-Fluorophenyl)-1-methyl-5-(2-acetamido-4-pyridyl)-2-methyl-thioimidazole

R1=—CH₃: Yield 63%

NMR (CDCl₃, ppm): 8.75 (bs, 1H), 8.26-8.24 (m, 2H), 7.46-7.39 (m, 2H), 6.97-6.88 (m, 3H), 3.53 (s, 3H), 2.71 (s, 3H), 2.23 (s, 3H)

IR (1/cm): 1669, 1607, 1543, 1505, 1416, 1268, 1218, 843

Example 62 4-(4-Fluorophenyl)-1-n-propyl-5-(2-acetamido-4-pyridyl)-2-methyl-thioimidazole

R1=—C₃H₇: Yield 28%

NMR (CDCl₃, ppm): 8.28-8.25 (m, 2H), 7.44-7.37 (m, 2H), 6.96-6.88 (m, 2H), 3.85 (t, 2H, J=7.7 Hz), 2.73 (s, 3H), 2.24 (s, 3H), 1.65-1.57 (m, 2H), 0.83 (t, 3H, J=7.4 Hz)

IR (1/cm): 3303, 1674, 1544, 1501, 1416, 1264, 1213, 845

Example 63 4-(4-Fluorophenyl)-1-(2,2,6,6-tetramethylpiperidin-4-yl)-5-(2-acetamido-4-pyridyl)-2-methylthioimidazole

R1=2,2,6,6-tetramethylpiperidin-4-yl: Yield 23%

NMR (CDCl₃, ppm): 10.62 (s, 1H), 8.38-8.35 (m, 2H), 8.01 (s, 1H), 7.33-7.26 (m, 2H), 7.04-6.95 (m, 3H), 4.19-4.03 (m, 1H), 2.61 (s, 3H), 2.00 (s, 3H), 1.87-1.81 (m, 2H), 1.52-1.47 (m, 2H), 0.93 (s, 6H), 0.78 (s, 6H)

IR (1/cm): 2976, 1699, 1533, 1407, 1255, 838

Example 64 4-(4-Fluorophenyl)-1-[3-(N-morpholino)propyl]-5-(2-acetamido-4-pyridyl)-2-methylthioimdazole

R1=N-morpholinopropyl-: Yield 52%

NMR (CDCl₃, ppm): 8.29 (m, 1H), 8.12 (s, 1H), 7.42-7.35 (m, 2H), 6.96-6.87 (m, 3H), 4.08-3.92 (m, 6H), 3.17-3.00 (m, 6H), 2.74 (s, 3H), 2.41-2.34 (m, 2H), 2.24 (s, 3H)

Example 65 4-(4-Fluorophenyl)-1-(3-hydroxypropyl)-5-(2-acetamido-4-pyridyl)-2-methylthioimidazole

R1=3-hydroxypropyl-: Yield 32%

NMR (CDCl₃, ppm): 8.69 (bs, 1H), 8.23-8.19 (m, 2H), 7.44-7.37 (m, 2H), 6.98-6.86 (m, 3H), 4.04 (t, 2H, J=7.9 Hz), 3.70 (t, 2H, J=7.2 Hz), 2.74 (s, 3H), 2.25 (s, 3H), 2.13-2.05 (m, 2H)

Example 66 4-(4-Fluorophenyl)-1-methyl-5-(2-amino-4-pyridyl)-2-methyl-thioimidazole

The compound of example 61 is dissolved in 10% strength HCl and refluxed for 14 h. After cooling, the mixture is neutralized with 20% strength NaOH. The resulting clear precipitate is filtered off and dried under reduced pressure over P₂O₅.

Yield: 82%

NMR (CDCl₃, ppm): 8.16-8.13 (m, 1H), 7.50-7.43 (m, 2H), 6.98-6.89 (m, 2H), 6.60-6.57 (m, 1H), 6.41 (s 1H), 4.60 (bs, 2H,) 3.46 (s, 3H), 2.70 (s, 3H)

IR (1/cm): 1629, 1542, 1509, 1215, 837, 814

Examples 67 to 69

The compound of example 66 is dissolved in abs. tetrahydrofuran (THF), and 1.2 times the amount of triethylamine is added. The reaction mixture is cooled in an ice-bath. With stirring, 1.2 times the amount of the acid chloride is added dropwise, and stirring is continued until no more starting material is present. The reaction mixture is filtered and the filtrate is concentrated to dryness. Purification of the crude product is carried out by column chromatography.

Example 67 4-([lacuna]-Fluorophenyl)-1-methyl-5-[2-(4-methoxybenzamido)-4-pyridyl]-2-methylthioimidazole

Yield: 62%

NMR (CDCl₃, ppm): 8.66 (s, 1H), 8.44 (s, 1H), 8.30 (s, 1H), 8.29-8.28 (m, 1H), 7.94-7.89 (m, 2H), 7.49-7.42 (m, 2H), 6.95-6.90 (m, 4H), 3.90 (s, 3H), 3.58 (s, 3H), 2.72 (s, 3H)

IR (1/cm): 3410, 1674, 1500, 1412, 1253, 1175, 840, 759

Example 68 4-([lacuna]-Fluorophenyl)-1-methyl-5-(2-cyclopropylamido-4-pyridyl)-2-methylthioimidazole

Yield: 24%

NMR (CDCl₃, ppm): 8.67-8.62 (m, 1H), 7.63-7.38 (m, 3H), 6.98-6.85 (m, 3H), 3.90 (s, 3H), 2.73 (s, 3H), 2.05-1.98 (m, 1H), 1.26-1.14 (m, 2H), 1.21-1.14 (m, 2H)

Example 69 4-([lacuna]-Fluorophenyl)-1-methyl-5-(2-cyclopentylamido-4-pyridyl)-2-methylthioimidazole

Yield: 53%

NMR (CDCl₃, ppm): 8.28-8.22 (m, 3H), 7.46-7.39 (m, 2H), 6.97-6.87 (m, 3H), 3.54 (s, 3H), 2.69 (s, 3H), 1.97-1.67 (m, 8H)

Examples 70 to 72

1.2 eq. of NaH are suspended in DMF, the compound of example 66 is added slowly and the reaction mixture is stirred at room temperature for 1 h. An equimolar amount of the benzyl bromide or phenylethyl bromide is added and the mixture is refluxed until no more starting material is present. The reaction mixture is diluted with water and the resulting precipitate is filtered off. The crude product is purified by column chromatography.

Example 70 4-(4-Fluorophenyl)-1-methyl-5-(2-benzylamino-4-pyridyl)-2-methyl-thioimidazole

Yield: 13%

NMR (CDCl₃, ppm): 8.12-8.16 (m, 1H), 7.47-7.26 (m, 7H), 6.95-6.86 (m, 2H), 6.53-6.50 (m, 1H), 6.24 (s, 1H), 5.30 (bs, 1H), 4.47 (d, 2H, J=5.8 Hz), 3.32 (s, 3H), 2.68 (s, 3H)

IR (1/cm): 3241, 1610, 1507, 1219, 839, 813, 737, 698

Example 71 4-(4-Fluorophenyl)-1-methyl-5-[2-(2-phenylethyl)amino-4-pyridyl]-2-methylthioimidazole

Yield: 54%

NMR (CDCl₃, ppm): 8.12-8.10 (m, 1H), 7.41-7.19 (m, 7H), 6.92-6.84 (m, 2H), 6.46-6.43 (m, 1H), 6.06 (s, 1H), 5.18 (d, 1H, J=6.3 Hz), 4.63-4.57 (m, 1H), 3.11 (s, 3H), 2.70 (s, 3H),

IR (1/cm): 1605, 1505, 1432, 1219, 839, 701

If 2.5 times the amount of benzyl bromide is added, the nitrogen (13) is disubstituted.

Example 72 4-(4-Fluorophenyl)-1-methyl-5-(2-dibenzylamino-4-pyridyl)-2-methyl-thioimidazole

Yield: 81%

NMR (CDCl₃, ppm): 8.27-8.24 (m, 1H), 7.45-7.19 (m, 12H), 6.95-6.86 (m, 2H), 6.51-6.48 (m, 1H), 6.31 (s, 1H), 4.80 (s, 4H), 3.17 (s, 3H), 2.66 (s, 3H)

IR (1/cm): 1598, 1496, 1427, 1219, 840, 831, 734, 702

Examples 73 to 75

The compound of examples 61, 62 or 63 is dissolved in THF and, with stirring, a 10-fold excess of LiAlH₄ is added. The reaction mixture is then heated for 2 h. After cooling, water is added slowly. The mixture is extracted repeatedly with CH₂Cl₂ and the combined organic phases are dried over Na₂SO₄. The drying agent is filtered off and the solvent is removed. The crude product is purified by column chromatography.

Example 73 4-(4-Fluorophenyl-1-methyl-5-(2-ethylamino-4-pyridyl)-2-methyl-thioimidazole

Yield: 70%

NMR (CDCl₃, ppm): 8.17-8.15 (m, 1H), 7.53-7.46 (m, 2H), 6.98-6.89 (m, 2H), 6.52-6.49 (m, 1H), 6.27-6.26 (m, 1H), 4.59 (t, 1H, J=6.0 Hz), 3.47 (s, 3H), 3.29-3.23 (m, 2H), 2.70 (s, 3H), 1.23 (t, 3H, J=7.1 Hz)

IR (1/cm): 3235, 1604, 1562, 1506, 1435, 1221, 844, 806

Example 74 4-(4-Fluorophenyl)-1-n-propyl-5-(2-ethylamino-4-pyridyl)-2-methylthioimidazole

Yield: 25%

NMR (CDCl₃, ppm): 8.17-8.14 (m, 1H), 7.51-7.43 (m, 2H), 6.98-6.87 (m, 2H), 6.53-6.50 (m, 1H), 6.27 (s, 1H), 4.61 (t, 1H, J=2.8 Hz), 3.79 (t, 2H, 7.7 Hz), 3.28-3.22 (m, 2H), 2.71 (s, 3H), 1.66-1.54 (m, 2H), 1.24 (t, 3H, J=7.2 Hz), 0.83 (t, 3H, J=7.4 Hz)

IR (1/cm): 3275, 2930, 1607, 1525, 1507, 1219, 846, 813

Example 75 4-(4-Fluorophenyl)-1-(2,2,6,6-tetramethylpiperidin-4-yl-5)-2-ethylamino-4-pyridyl)-2-methylthioimidazole

Yield: 52%

NMR (CDCl₃, ppm): 8.10-8.07 (m, 2H), 7.47-7.40 (m, 2H), 7.12-7.03 (m, 2H), 6.44-6.41 (m, 1H), 6.37 (s, 1H), 4.30-4.14 (m, 1H), 3.27-3.21 (m, 2H), 2.66 (s, 3H), 2.11-1.91 (m, 2H), 1.59-1.52 (m, 2H), 1.12-1.01 (m, 9H), 0.90 (s, 6H)

IR (1/cm): 3325, 2959, 1603, 1516, 1499, 1217, 1158, 849, 812

Example 76 4-(4-Fluorophenyl)-1-(3-N-morpholinopropyl)-5-(2-acetamido-4-pyridyl)-2-(4-methylsulfinylbenzyl)thioimidazole

Under protective gas, 4-(4-fluorophenyl)-1-(3-N-morpholinopropyl)-5-(2-acetamido-4-pyridyl)imidazole-2-thione is suspended in abs. ethanol and an equimolar amount of 4-methylsulfinylbenzyl chloride is added. A spatula tip of Na₂CO₃ is added and the reaction mixture is then refluxed until the starting material has been converted completely. After cooling, the inorganic salts are filtered off and the solvent is removed using a rotary evaporator. The crude product is purified by column chromatograpy.

Yield: 27%

NMR (CDCl₃, ppm): 8.67 (bs, 1H), 8.28-8.25 (m, 2H), 8.12 (s, 1H), 7.64-7.49 (m, 4H), 7.44-7.37 (m, 2H), 6.98-6.86 (m, 3H), 4.45 (s, 2H), 3.81-3.65 (m, 6H), 2.72 (s,3H), 2.54-2.52 (m, 6H), 2.22 (s, 3H), 1.85-1.73 (m, 2)

Using the process described above, the following compounds were obtained:

Example R¹ R² 77 cyclo-C₆H₁₁ CH₃ 78 —(CH₂)₂—N(CH₃)₂ CH₃ 79 —(CH₂)₃—OH CH₃ 80 —(CH₂)₃—OCH₃ CH₃ 81 CH₃ —(CH₂)₂ S CH₃ 82 CH₃ —(CH₂)₂ SO CH₃ 83 cyclo-C₆H₁₁ CH₂-Ph-4-SO CH₃ 84 cyclo-C₆H₁₁ CH₂-Ph-4-SCH₃

Example R1 R7 R8 85

COCH₃ H 86

C₂H₅ H 87 n-C₃H₇ H H 88 CH₃ benzyl benzyl 

1. A 2-thio-substituted imidazole derivative of the formula I

wherein R¹ is selected from the group consisting of: C₁-C₆-alkyl which is unsubstituted or substituted by one or two hydroxyl or C₁-C₄-alkoxy groups or by a nonaromatic heterocyclic radical having 5 or 6 ring atoms and 1 or 2 heteroatoms independently of one another selected from the group consisting of N, O and S, C₂-C₆-alkenyl, C₃-C₆-cycloalkyl, aryl which is unsubstituted or substituted by one or more halogen atoms or by a C₁-C₄-alkylsulfanyl group, amino-C₁-C₄-alkyl, where the amino group is unsubstituted or substituted by one or two C₁-C₄-alkyl groups, aminoaryl, where the amino group is unsubstituted or substituted by one or two C₁-C₄-alkyl groups, aryl-C₁-C₄-alkyl and an aromatic or nonaromatic heterocyclic radical having 5 or 6 ring atoms and 1 or 2 heteroatoms independently of one another selected from the group consisting of N, O and S, which heterocyclic radical is unsubstituted or substituted by 1, 2, 3 or 4 C₁-C₄-alkyl groups, an aryl or aryl-C₁-C₄-alkyl group, R² is selected from the group consisting of: C₁-C₆-alkyl, phenyl-C₁-C₄-alkyl, where the phenyl group may have one or two substituents independently of one another selected from the group consisting of C₁-C₄-alkyl, halogen, C₁-C₄-alkylsulfanyl, C₁-C₄-alkylsulfinyl and C₁-C₄-alkylsulfonyl, C₂-C₆-alkenyl, C₂-C₆-alkenyl which is substituted by one or two halogen atoms and/or phenyl groups, where the phenyl group may independently be substituted by one or two C₁-C₄-alkyl or halogen atoms, C₂-C₆-alkynyl, C₂-C₆-alkynyl which is substituted by a phenyl group which may be unsubstituted or substituted by one or two C₁-C₄-alkyl or halogen atoms, C₁-C₆-alkyl which is substituted by a nonaromatic heterocyclic radical having 5 or 6 ring atoms and 1 or 2 heteroatoms independently of one another selected from the group consisting of N, O and S, C₁-C₄-alkylsulfanyl, C₁-C₄-alkylsulfinyl or C₁-C₄-alkylsulfonyl, phenyl and phenyl which has one or two substituents independently of one another selected from the group consisting of C₁-C₄-alkyl, halogen, C₁-C₄-alkylsulfanyl, C₁-C₄-alkylsulfinyl and C₁-C₄-alkylsulfonyl, or R¹ and R² together are —CH₂CH₂— or —CH₂CH₂CH₂—, R³ is halogen substituted phenyl, R⁴ is 4-pyridyl which is substituted by amino, C₁-C₄-alkylamino, phenyl-C₁-C₄-alkylamino or R⁵CONR⁶—, where R⁵ is C₁-C₄-alkyl, phenyl, which may have one or two substituents independently of one another selected from the group consisting of C₁-C₄-alkyl, C₁-C₄-alkoxy and halogen, or C₃-C₆-cycloalkyl and R⁶ is H, C₁-C₄-alkyl or benzyl, and with the proviso that, if R¹ represents aryl-C₁-C₅-alkyl or amino-C₁-C₆-alkyl, where the amino group is unsubstituted or substituted by one or two C₁-C₄-alkyl groups, R² represents alkylsulfonyl- or alkylsulfinylaryl-C₁-C₅-alkyl, or an optical isomer or physiologically acceptable salt thereof.
 2. A compound as claimed in claim 1, wherein the pyridyl is substituted in 2-position.
 3. A compound as claimed in claim 1, wherein R⁴ is 4-pyridyl which is substituted by phenyl-C₁-C₄-alkylamino.
 4. A compound as claimed in claim 1, wherein R³ is 4-fluorophenyl.
 5. A compound of the formula I as claimed in claim 1, wherein R¹ is C₁-C₃-alkyl, C₃-C₆-cycloalkyl or 2,2,6,6-tetramethylpiperidinyl.
 6. A compound as claimed in claim 5, wherein R¹ is C₁-C₃-alkyl or 2,2,6,6-tetramethylpiperidinyl.
 7. A compound of the formula I as claimed in claim 1, wherein R² is C₁-C₆-alkyl or phenyl-C₁-C₄-alkyl, where the phenyl group is substituted by C₁-C₄-alkylsulfanyl, C₁-C₄-alkylsulfinyl or C₁-C₄-alkylsulfonyl.
 8. A compound of the formula I as claimed in claim 1, wherein R¹ is C₁-C₆-alkyl which is unsubstituted or substituted by one or two hydroxyl or C₁-C₄-alkoxy groups, or a nonaromatic heterocyclic radical having 5 or 6 ring atoms and 1 or 2 heteroatoms independently of one another selected from the group consisting of N, O and S, C₃-C₆-cycloalkyl or an aromatic or nonaromatic heterocyclic radical having 5 or 6 ring atoms and 1 or 2 heteroatoms independently of one another selected from the group consisting of N, O and S, which heterocyclic radical is unsubstituted or substituted by 1, 2, 3 or 4 C₁-C₄-alkyl groups, an aryl or aryl-C₁-C₄-alkyl group, R² is, C₁-C₆-alkyl, phenyl-C₁-C₄-alkyl, where the phenyl group may have one or two substituents independently of one another selected from the group consisting of C₁-C₄-alkyl, halogen, C₁-C₄-alkylsulfanyl, C₁-C₄-alkylsulfinyl and C₁-C₄-alkylsulfonyl, phenyl, C₁-C₆-alkyl substituted by a nonaromatic heterocyclic radical having 5 or 6 ring atoms and 1 or 2 heteroatoms independently of one another selected from the group consisting of N, O and S, C₁-C₄-alkylsulfanyl, C₁-C₄-alkylsulfinyl or C₁-C₄-alkylsulfonyl, or is phenyl which has one or two substituents independently of one another selected from the group consisting of C₁-C₄-alkyl, halogen, C₁-C₄-alkylsulfanyl, C₁-C₄-alkylsulfinyl and C₁-C₄-alkylsulfonyl, R¹ and R² together are —CH₂CH₂— or —CH₂CH₂CH₂—, R³ is halogen substituted phenyl, and R⁴ is 4-pyridyl which is substituted by amino, C₁-C₄-alkylamino, phenyl-C₁-C₄-alkylamino or R⁵CONR⁶—, where R⁵ is C₁-C₄-alkyl, phenyl which may have one or two substituents independently of one another selected from the group consisting of C₁-C₄-alkyl, C₁-C₄-alkoxy and halogen, or C₃-C₆-cycloalkyl and R⁶ is H, C₁-C₄-alkyl or benzyl, or an optical isomer or physiologically acceptable salt thereof.
 9. A compound as claimed in claim 8, wherein R¹ is C₁-C₃-alkyl, C₃-C₆-cycloalkyl or 2,2,6,6-tetramethylpiperidinyl.
 10. A compound as claimed in claim 8, wherein R² is C₁-C₆-alkyl or phenyl-C₁-C₄-alkyl, where the phenyl group is substituted by C₁-C₄-alkylsulfanyl, C₁-C₄-alkylsulfinyl or C₁-C₄-alkylsulfonyl.
 11. A compound as claimed in claim 8, wherein R⁴ is 4-pyridyl which is substituted by phenyl-C₁-C₄-alkylamino.
 12. A pharmaceutical composition, comprising at least one compound as claimed in claim 1, together with one or more pharmaceutically acceptable carriers and/or additives. 